Abstract

Flavonoids are polyphenolic compounds naturally occurring in fruits and vegetables, in addition to beverages such as tea and coffee. Flavonoids are emerging as potent therapeutic agents for cardiovascular as well as metabolic diseases. Several studies corroborated an inverse relationship between flavonoid consumption and cardiovascular disease (CVD) or adipose tissue inflammation (ATI). Flavonoids exert their anti-atherogenic effects by increasing nitric oxide (NO), reducing reactive oxygen species (ROS), and decreasing pro-inflammatory cytokines. In addition, flavonoids alleviate ATI by decreasing triglyceride and cholesterol levels, as well as by attenuating inflammatory mediators. Furthermore, flavonoids inhibit synthesis of fatty acids and promote their oxidation. In this review, we discuss the effect of the main classes of flavonoids, namely flavones, flavonols, flavanols, flavanones, anthocyanins, and isoflavones, on atherosclerosis and ATI. In addition, we dissect the underlying molecular and cellular mechanisms of action for these flavonoids. We conclude by supporting the potential benefit for flavonoids in the management or treatment of CVD; yet, we call for more robust clinical studies for safety and pharmacokinetic values.

Introduction

The leading cause of morbidity and mortality worldwide is cardiovascular disease (CVD) [1], with atherosclerosis being the major contributor to this mortality [2]. Atherosclerosis is the chronic inflammation of the intima in middle-sized and large arteries [2]. It is characterized by leukocyte infiltration, lipid accumulation, foam cell formation, endothelial dysfunction, in addition to vascular smooth muscle cell (VSMC) proliferation and migration [3]. Despite the preventable nature of atherosclerosis [4], its incidence is expected to continuously increase [1,5]. This increase is associated with an unhealthy lifestyle that further increases the risk of atherosclerosis [6]. Specifically, the world is witnessing nutritional transition, with shifting dietary habits towards unhealthy food choices [7]. Relevantly, data from Behavioral Risk Factor Surveillance showed that only 5% of adults adhered to all of the three healthy behaviors: physical activity, fruit and vegetable consumption, and nonsmoking [8]. In addition, WHO reported a great burden of over-nutrition [9]. This unhealthy diet, combined with absence of physical activity, leads to obesity, which in turn sets the stage for adipose tissue dysfunction, namely adipose tissue inflammation (ATI) [4,5].

Adipose tissue inflammation (ATI) is a condition characterized by increased amount of adipose tissue, initiating signaling from fat to vessels [10]. The identification of adipose tissue not only as fat storage cells but also as proper endocrine system contributing to vascular inflammation is key to understanding the pathology of atherosclerosis and ATI.

Indeed, adipose tissue is an important source of adipokines, including tumor necrosis factor alpha (TNF-α), interleukin 1 beta (IL-1β), interleukin 6 (IL-6), protein monocyte chemotactic (MCP-1) and C-reactive protein (CRP) [11,12]. Secretion of these adipokines enhances vascular inflammation and alters vascular function [10]. In addition, accumulated adipose tissue largely contributes to the levels of leptin and adiponectin [10]. These hormones play a major role in fatty acid synthesis and oxidation, two key processes in ATI [12]. As such, ATI is not a consequence of atherosclerosis, but rather a major contributor to the disease [11].

Adipose tissue is dispersed throughout the body, and categorized into subcutaneous adipose tissue (SAT), visceral adipose tissue (VAT), and perivascular adipose tissue (PVAT) [13]. There is substantial evidence linking inflammation in adipose tissue, be it perivascular, visceral, or subcutaneous to atherosclerosis. Relevantly, an increase in adiposity is linked to higher atherogenicity [14].

Perivascular adipose tissue (PVAT) is the fat surrounding blood vessels [15]. PVAT are well documented to secrete vasoreactive gases, cytokines, and adipokines [16]. Owing to their close proximity to blood vessels, PVAT-secreted adipokine elicits a paracrine effect on the vascular tissue, thus playing a major role in vascular homeostasis [17]. Under normal conditions, PVAT plays an anti-atherogenic role by enhancing endothelial function and vasorelaxant effect and decreasing oxidative stress [16]. However, certain pathophysiological conditions, such as obesity, cause PVAT dysfunction leading to imbalanced secretome [15]. Particularly, there is a decrease in protective adipokines namely adiponetctin, vaspin, apelin, and ometin-1 [16]. In fact, adiponectin deficiency increases leukocyte–endothelium interactions by up-regulating adhesion molecules [18]. In addition, adeponectin is known to decrease ROS levels and to down-regulate pro-inflammatory factors [19,20]. As such, a decrease in adiponectin level will compromise its vasculoprotective effect. Similarly, the down-regulation of vaspin, apelin, and omentin-1 will attenuate their anti-atherogenic effects, ROS scavenging, promoting cholesterol efflux, and reducing macrophage activation, respectively [21–23]. On the other hand, PVAT dysfunction causes an increase in pro-atherogenic adipokines such as leptin, resistin, chemirin, and visfatin [16]. In fact, leptin is known to promote VSMC phenotypic switch by activating p38 MAPK and aggravate endothelial dysfunction in a PKC-dependent manner. Other atherogenic events such as macrophage maturation, leukocyte infilteration, and endothelial dysfunction are stimulated by PVAT-secreted resistin, chemirin, and visfatin [24,25]. Taken together, these studies support an adipose tissue-vascular cross-talk by which PVAT promotes atherosclerosis [11] (Figure 1).

Adipose tissue-vascular cross-talk

Figure 1
Adipose tissue-vascular cross-talk

Increased oxidative stress and obesity create a pathological inflammatory response at the level of adipose tissue, manifested through increased release of pro-inflammatory mediators, recruitment of leukocytes and impairment of adipogenesis, adipocyte lipid metabolism, and adipocyte apoptosis. This also generates aberrant responses at the level of the vasculature such as increased VSMC proliferation, endothelial dysfunction and inflammatory mediators release, all of which in turn contribute to further inflammation and atherosclerosis development.

Figure 1
Adipose tissue-vascular cross-talk

Increased oxidative stress and obesity create a pathological inflammatory response at the level of adipose tissue, manifested through increased release of pro-inflammatory mediators, recruitment of leukocytes and impairment of adipogenesis, adipocyte lipid metabolism, and adipocyte apoptosis. This also generates aberrant responses at the level of the vasculature such as increased VSMC proliferation, endothelial dysfunction and inflammatory mediators release, all of which in turn contribute to further inflammation and atherosclerosis development.

Visceral adipose tissue (VAT) also contributes to atherosclerosis [26]. Like PVAT, VAT is an important source of adipokines including leptin, adiponectin, TNF-α, and MCP-1 [27], whose dysregulation plays a role in vascular inflammation [28]. In fact, there exists a paracrine loop between adipocyte and macrophages via secreted FFA and TNF-α, respectively [29]. This loop is postulated to exacerbate atherosclerosis [29,30]. It has been reported that pro-inflammatory cytokines, MCP-1 and IL-6, are up-regulated and the anti-inflammatory cytokine adiponectin is down-regulated in adipocyte/macrophage co-culture [29]. In addition, VAT produces several pro-inflammatory, TNF-α, IL-6, and MCP-1 [30]. In vivo experiments showed that obesity induces iNOS, TNF-α, and CCR2 expression by monocyte/macrophages [30,31]. Furthermore, adipocytes of obese individuals secrete IL-6, and this secretion is correlated with adiposity [32].

Both subcutaneous and visceral adipose tissues contribute to atherogenesis [33]. A clinical study showed that obesity-induced pro-inflammatory changes in a subcutaneous adipose are associated with infiltration of macrophage and up-regulation of IL-6, TNF-α, MCP-1, and IP-10 cytokine expression, leading to vascular dysfunction [14,34]. However, VAT and PVAT were reported to have higher pro-inflammatory effect than SAT [35]. In addition, it has been reported that proinflammatory mediators such as TNF-α, leptin, adiponectin, resistin, PAI-1, apelin, IL-6, resistin, and CRP, are more released by VAT than by SAT [36,37].

Taken together, these studies support an interplay between adipose tissue and atherosclerosis. As such, an optimal treatment would be one that targets the adipose-vascular axis.

To date, some drugs have shown improvements in cardiovascular outcomes in diseases associated with atherosclerosis such as coronary heart disease. For example, statin therapy reduces major adverse cardiovascular events including myocardial infarctions, strokes and all-cause mortality in patients with or at risk for atherosclerotic cardiovascular disease [38–40]. These drugs target various molecules involved in the pathogenesis of these conditions. As ATI could be one of the major contributing factors to the pathogenesis of atherosclerosis, one could foresee a scenario where drugs that potentially interfere with signaling events that could exacerbate ATI and atherosclerosis may be beneficial. In addition to pharmacological interventions, a substantial amount of evidence has supported the therapeutic potential of medicinal plants for the treatment of various CVDs [41–43]. Notably, most of these plants’ anti-atherosclerotic and anti-adipose tissue inflammatory may be elicited by flavonoids and flavonoid-rich extracts [44]. Accordingly, this group of naturally occurring chemicals may present an attractive therapeutic potential in the prevention and management of atherosclerosis and ATI.

Flavonoids are a family of polyphenolic compounds found in many plants, fruits, vegetables, grains and tea (Table 1). Traditionally, flavonoids are subdivided into six primary sub-groups: flavones, flavonols, flavan-3-ols (flavanols), flavanones, anthocyanins, and isoflavones [45]. Although these subclasses share a common diphenylpropane skeleton (C6-C3-C6), they are structurally diverse and as such, produce a wide range of effects through their antioxidant, anti-inflammatory and/or antithrombotic activities [46,47].

Table 1
Structures and food sources of main flavonoid subgroups
FlavonoidStructureDietary source
Flavone  • Tangerines
• Oranges
• Celery
• Garlic
• Chamomile
• Tea 
Flavonol  • Onions
• Broccoli
• Tea
• Fruits 
Flavanol (flavan-3-ol)  • Apples
• Pears
• Cocoa
• Tea
• Grape 
Flavanone  • Citrus fruits peels 
Anthocyanin  • Berries
• Currants grapes
• Black carrot
• Red cabbage
• Purple potato 
Isoflavone  • Soy
• Legumes 
FlavonoidStructureDietary source
Flavone  • Tangerines
• Oranges
• Celery
• Garlic
• Chamomile
• Tea 
Flavonol  • Onions
• Broccoli
• Tea
• Fruits 
Flavanol (flavan-3-ol)  • Apples
• Pears
• Cocoa
• Tea
• Grape 
Flavanone  • Citrus fruits peels 
Anthocyanin  • Berries
• Currants grapes
• Black carrot
• Red cabbage
• Purple potato 
Isoflavone  • Soy
• Legumes 

Substantial body of clinical evidence points toward the cardio-vasculoprotective roles of flavonoids [48–53]. These bountiful health effects of flavonoids may partly explain the interest in herbal medicine of CVD [52,54–57], especially that molecular mechanisms of the cardio-vasculoprotective effects of many herbs/plants have been established [41,42,58,59]. Recent meta-analyses demonstrated that high consumption of total flavonoids was associated with decreased CVD risk [51] and associated mortality [48–50]. Mechanistically, these compounds impart their protective effects on atherosclerosis via numerous mechanisms, including enhancement of nitric oxide (NO) bioavailability, reduction of reactive oxygen species (ROS), and amelioration of nuclear factor kappa-light-chain-enhancer of activated B-cells (NF-κB) mediated inflammatory responses. In addition to this, flavonoids attenuate ATI by targeting multiple signaling pathway products such as adenosine monophosphate activated protein kinase (AMPK), mitogen-activated protein kinase (MAPK), peroxisome proliferator-activated receptor alpha (PPARα), peroxisome proliferator-activated receptor gamma (PPARγ), toll-like receptor 2 (TLR2) and toll-like receptor 4 (TLR4), resulting in beneficial outcomes on triglyceride and cholesterol levels, inflammation and adipogenesis. In this review, we discuss the effects of the six main classes of flavonoids on atherosclerosis and ATI.

Flavonoids

Flavones

Flavones are found in many plants including citrus fruits, celery, parsley, in addition to chamomile and Ginkgo biloba [60]. Due to their widely studied effects on ATI and atherosclerosis, three flavones, luteolin, nobiletin, and tangeretin, will be discussed here (Figure 2).

Flavonoid effects on endothelial dysfunction and inflammation in atherosclerosis

Figure 2
Flavonoid effects on endothelial dysfunction and inflammation in atherosclerosis

Flavonoids including quercetin, kaempferol, luteolin, naringenin, genistein, anthocyanin, epicatechin and daidzien decrease oxidative stress in endothelial cells through decreasing NADPH activity or increasing activity of antioxidant systems. This, in turn, ameliorates endothelial dysfunction and reduces the oxidation of LDL-C particles. In addition, the flavonoids quercetin, EGCG, kaempferol, genistein, epicatechin and anthocyanins reduce NF-κB activation through multiple pathways, one of which is through inhibition of TLR receptors. Inhibition of NF-κB activity ameliorates the inflammatory response through decreased production of adhesion molecules, recruitment of inflammatory cells such as monocytes and subsequent prevention foam cell formation and further production of inflammatory cytokines.

Figure 2
Flavonoid effects on endothelial dysfunction and inflammation in atherosclerosis

Flavonoids including quercetin, kaempferol, luteolin, naringenin, genistein, anthocyanin, epicatechin and daidzien decrease oxidative stress in endothelial cells through decreasing NADPH activity or increasing activity of antioxidant systems. This, in turn, ameliorates endothelial dysfunction and reduces the oxidation of LDL-C particles. In addition, the flavonoids quercetin, EGCG, kaempferol, genistein, epicatechin and anthocyanins reduce NF-κB activation through multiple pathways, one of which is through inhibition of TLR receptors. Inhibition of NF-κB activity ameliorates the inflammatory response through decreased production of adhesion molecules, recruitment of inflammatory cells such as monocytes and subsequent prevention foam cell formation and further production of inflammatory cytokines.

Luteolin

A large body of evidence supports the atheroprotective potential of luteolin (Figure 2). A recent study showed that luteolin alleviated vascular endothelial injury in atherosclerotic rats by decreasing the expression of intracellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) in aortic tissue [61]. Furthermore, luteolin-administrated rats exhibited lower serum levels of the pro-inflammatory cytokines TNF-α, IL-6, and CRP [61]. This decrease was concomitant with increased levels of serum superoxide dismutase (SOD) and NO, both of which are known to affect vascular function [61]. Moreover, in both high fat diet (HFD) rats and atherosclerotic low-density lipoprotein receptor knockout (ldlr−/−) mice, luteolin was able to decrease serum levels of cholesterol, triglyceride and LDL [61,62]. Knowing that ATI is characterized by high plasma levels of cholesterol, triglyceride, and LDL [63], luteolin may thus present a promising therapeutic compound in the realm of ATI treatment. In vitro, luteolin attenuated key cellular events contributing to atherosclerosis [64]. For instance, luteolin inhibited hydrogen peroxide-induced induced VSMC proliferation and migration by down-regulating Akt and Src phosphorylation [65,66] (Figure 3). This inhibition of Src in turn abolished NF-κB translocation, thereby suppressing inflammatory responses in VSMCs [67]. As such, luteolin inhibited oxidative stress exerted by H2O2 on VSMCs. In addition, luteolin inhibited NF-κB and Nox4 leading to decreased ROS production in HUVECs [68]. Luteolin attenuated cell adhesion by suppressing endothelial ICAM-1 and VCAM-1 [69] in a p38-dependent manner (Figure 2). In macrophages, which are known to contribute to the pathogenesis of neointima, luteolin's anti-inflammatory effects were attributed to its ability to reduce p38-mediated TNF-α and IL-6 expression [70]. This anti-inflammatory effect of luteolin is also attributed to its an antioxidant-independent capacity to attenuate Src phosphorylation, thus inhibiting NF-κB signaling in macrophages [67]. Indeed, luteolin could attenuate foam cell formation by decreasing lipid accumulation in macrophages [71] (Figure 2). The capacity of luteolin to reduce foam cell formation may suggest an ATI reversing potential of this flavone [72].

Effects of flavonoids on vascular smooth muscle cells
Figure 3
Effects of flavonoids on vascular smooth muscle cells

Flavonoids including luteolin decrease proliferation, migration and inflammatory responses of VSMCs via Akt down-regulation and inhibition of NF-κB translocation.

Figure 3
Effects of flavonoids on vascular smooth muscle cells

Flavonoids including luteolin decrease proliferation, migration and inflammatory responses of VSMCs via Akt down-regulation and inhibition of NF-κB translocation.

A critical analysis of the luteolin-mediated anti-inflammatory effects shows that they may be mediated by decreasing oxidative stress or by targeting some other players. The cardioprotective effect of luteolin may be elicited by enhancing the antioxidant capacity through inducting HO-1 [73] or attenuating ROS-activated MAPK [74]. On the other hand, luteolin’s anti-inflammatory effects may also be mediated by enhancing d mRNA stability through p38/MK2/TTP-regulated pathway [70], inducing autophagy by increasing Beclin-1 activity and LC3-II/LC3-I ratio [71].

Both in vitro and in vivo studies show that luteolin-induced down-regulation of adhesion molecules, specifically ICAM-1 and VCAM-1, attenuated cell adhesion, a key event in atherosclerosis [68,75] Furthermore, luteolin attenuated pro-inflammatory cytokines in both models [70,75]. These protective effects present luteolin as a potent therapy to atherosclerosis and ATI. However, a limitation is that these studies focused on basic research. Therefore, clinical trials are needed to better assess the clinical utilization of luteolin and assure its efficacy.

Nobiletin

Nobiletin is another flavone with well-documented anti-inflammatory effects at the levels of vasculature and adipose tissue. In line with this notion, nobiletin attenuated dyslipidemia and atherosclerosis in ldlr −/− mice and in C57BL/6J mice [76,77]. This effect was elicited by enhancing fatty acid β-oxidation and reducing very low-density liporotein-triglyceride (VLDL-TG) and cholesterol [76,77]. Nobiletin also decreased aortic cholesterol and reduced macrophage content in atherosclerotic lesion of ldlr−/− mice [78,79]. Furthermore, nobiletin reduced the number and the size of fat droplets in liver [77]. This effect appears to be mediated by nobiletin-induced phosphorylation of hepatic AMPK and its downstream target acetyl-Coenzyme carboxylase (ACC) [80]. In addition, nobiletin attenuated high fat diet-induced ATI via suppression of pro-inflammatory genes (NF‐κB, TNF‐α, TLR2, and TLR4) and up-regulating fatty acid (FA) oxidation genes, PPARα and carnitine palmitoyltransferase 1A (CPT1a) [77] (Figures 2 and 4).

Flavonoid effects on reverse cholesterol transport and adipose tissue inflammation
Figure 4
Flavonoid effects on reverse cholesterol transport and adipose tissue inflammation

Flavonoids such as quercetin, kaempferol and hesperedin improve RCT and metabolic profile through up-regulation of ABCAl and ABCG1 through p38-dependent pathways or other unidentified mechanisms. This promotes cholesterol efflux from macrophages and inhibits foam cell formation. Hesperidin has also been shown to up-regulate hepatic ABCG8, further contributing to improved RCT, as well as lowering hepatic lipid content. In adipocytes, nobiletin ameliorates fat diet-induced ATI via suppression of NF‐κB and down-regulation of pro-inflammatory cytokine levels in plasma.

Figure 4
Flavonoid effects on reverse cholesterol transport and adipose tissue inflammation

Flavonoids such as quercetin, kaempferol and hesperedin improve RCT and metabolic profile through up-regulation of ABCAl and ABCG1 through p38-dependent pathways or other unidentified mechanisms. This promotes cholesterol efflux from macrophages and inhibits foam cell formation. Hesperidin has also been shown to up-regulate hepatic ABCG8, further contributing to improved RCT, as well as lowering hepatic lipid content. In adipocytes, nobiletin ameliorates fat diet-induced ATI via suppression of NF‐κB and down-regulation of pro-inflammatory cytokine levels in plasma.

The modulatory effect of nobiletin on ATI is further mirrored in vitro in hepatic cells and macrophages. In HepG2 cells, nobiletin decreased the expression of diacylglycerol O-acyltransferase 1 and 2 (DGAT1 and DGAT2), thus inhibiting apolipoprotein B-100 (ApoB-100) secretion via extracellular signal-regulated kinase 1 and 2 (ERK1/2) activation [76]. In macrophages, nobiletin inhibited class A scavenger receptor-mediated metabolism of acetylated LDL [81], which is a marker of foam cell formation [82]. Taken together, these findings provide a glimpse on the potential role of nobiletin in the pathogenesis of ATI.

The signaling pathways activated by nobiletin in vivo differ from those activated in vitro. Nonetheless, in both models, nobiletin affected lipoprotein levels and cholesterol metabolism. Unfortunately, studies assessing the effect of nobiletin in human subjects are still needed.

Tangeretin

Evidence documenting the protective effect of tangeretin against atherosclerosis and dyslipidemia is on the rise. Tangeretin is speculated to reduce ATI by virtue of its capacity to lower serum cholesterol and TG, as evident in hamsters with diet-induced hypercholesterolemia [83]. In addition, tangeretin administration decreased body weight and plasma lipids of diabetic rats [84]. Furthermore, tangeretin decreased cardiac lipid peroxidation and inflammatory cytokines TNF-α, IL-6, CRP, and NF-κB in the serum of these rats [84] (Figure 2).

The anti-atherosclerotic effects of tangeretin could be attributed to its ability to reduce ApoB secretion, cholesterol synthesis, triacylglycerol (TAG) synthesis, and lipid metabolism [85,86]. This appears to be due to decreased activities of diacylglycerol (DAG) acyltransferase and microsomal triglyceride transfer protein [86]. In addition, tangeretin attenuated lipid and triglyceride accumulation in 3T3-L1 adipocytes [87]. Moreover, tangeretin attenuated thrombus formation via inhibition of platelet activation and aggregation through inhibiting integrin αIIbβ3 integrin modulation [88] (Figure 2). These effects were mediated by increased cyclic guanosine monophosphate (cGMP) levels and decreased Akt phosphorylation [88]. The aforementioned effects of tangeretin strongly support its beneficial effect in the prevention or treatment of ATI.

A comparative observation of the anti-inflammatory/anti-atherogenic effect of tangeretin reveals some common effects among various models. For instance, tangeretin decreased cholesterol levels in human subjects and attenuated cholesterol synthesis in vitro. Furthermore, tangeretin decreased body weight and plasma lipids in vivo. This effect is translated in vitro by decreased TAG and lipid accumulation.

It is worth mentioning that nobiletin and tangeretin have a great antioxidant potential. These two flavonoids were able to decrease lipid peroxidation and ROS in Saccharomyces cerevisiae model. In addition, they were able to activate cytosolic catalase in mutant strains deficient in glutathione synthase, catalase, or superoxide dismutase [89]. These results provide perspective towards prescribing dietary antioxidants, namely nobiletin and tangeretin, in an attempt to prevent/treat oxidative-related diseases such as atherosclerosis. Indeed, clinical trials are warranted to validate this approach and determine the downstream effectors.

Flavonols

Flavonols are very widely distributed and abundant in the human diet [90]. The major flavonols include quercetin and kaempferol, which naturally exist as different glycosides [45], found in onions, broccoli, apples, green tea and black grapes [91]. Evidence suggests that flavonols exert their cardioprotective benefits through improvement of metabolic profiles, inflammatory conditions, redox states, and endothelial dysfunction [51,92].

Quercetin

Quercetin is the most extensively studied flavonol. It modulates a wide range of pathophysiologic states including inflammation, oxidative stress, cancer, allergy, and lipid metabolism [93–96]. These effects render quercetin a promising bioactive for atherosclerosis management or therapy.

In the context of ATI, the antioxidant effects of quercetin are especially important. It is known that in conditions of oxidative stress, excessive ROS generation induces inflammation, and atherogenesis [97]. Interestingly, a growing body of evidence indicates that ATI is associated with a state of chronic, low-grade systemic inflammation that further increases atherogenic potential [98,99]. Moreover, obesity, which is characterized by the accumulation of fat, is a well-known atherosclerotic risk factor [100]. Taken together, these data suggest that an antioxidant compound like quercetin may alleviate ATI.

In agreement with the above, quercetin has been shown to ameliorate ATI through the reduction of oxidative stress-induced inflammation. A major pro-inflammatory transcription factor that is activated in response to oxidative stress is NF-κB. In this context, quercetin reversed the abnormal lipid profile, and decreased NF-κB activation through suppression of ROS overproduction in multiple rat models [101,102]. Contextually, an important effect downstream of NF-κB signaling is enhanced endothelial–leukocyte interaction. This is mediated by increased release of pro-inflammatory cytokines and expression of adhesion molecules on activated endothelial cells. Interestingly, macrophage recruitment and infiltration may also occur in adipose tissue through the actions of these inflammatory mediators [99,103], further contributing to atherosclerosis [104]. As such, quercetin supplementation in apolipoprotein E (ApoE−/−) mice suppressed Src/Akt/NF- κB signaling leading to a down-regulation of pro-inflammatory interleukin-6 (IL‐6) and interleukin-12 (IL‐12) [105]. This anti-inflammatory effect of quercetin was also seen in C5BL/6J mice with suppression of interferon γ (IFNγ), TNF-α, interleukin-1 (IL-1), and interleukin-4 (IL-4) [94]. Moreover, quercetin attenuated co‐stimulators cluster of differentiation 80, 86 (CD80, CD86) as well as significantly reduced atherosclerotic lesion size [105], decreased lipid deposition, and reduced macrophage and T-cell infiltration [95]. In oxidized LDL (ox-LDL) treated human umbilical endothelial cells (HUVECs), quercetin significantly reduced expression of VCAM-1 and ICAM-1 by decreasing activation of the TLR-NF-κB signaling [106] (Figure 2). From this, it is possible to expect that quercetin’s ability to decrease the systemic levels of pro-inflammatory mediators may be extended to alleviate ATI and adipocyte–leukocyte cell interaction. Interestingly, quercetin appears to influence inflammation-induced interactions between adipocytes and macrophages. Macrophages treated with quercetin exhibited a decreased capacity to infiltrate into adipose tissue and inflame adipocytes through decreased inflammatory gene expression. These effects were accompanied by reduced insulin resistance via enhancement of insulin-stimulated glucose uptake [107].

Other mechanisms in which quercetin may exert its biological effects is through regulation of fat production and metabolism. Quercetin has been shown to suppress adipogenesis and enhance adipocyte apoptosis through several mechanisms [108–111] some of which may be ROS-dependent [112]. This property of quercetin challenges ongoing adipocyte hypertrophy and possible hyperplasia that are known to increase aberrant production of ROS and secretion of pro-inflammatory and pro-thrombotic mediators [113].

Quercetin has also been shown to play a role in adipogenesis and regulation of fat accumulation, via gene level regulation. Specifically, quercetin suppressed adipogenesis in 3T3-L1 pre-adipocytes by reducing the key adipogenic factor CCAAT/enhancer binding protein (C/EBP α) mRNA levels, and reduced lipogenesis by down-regulating the gene levels of fatty acid synthase (FAS) and ACC [109]. Moreover, quercetin can also mediate its effects through inducing apoptosis in adipocytes via ERK and c-jun-N-terminal kinase (JNK) pathways [110]. Quercetin also inhibits TNF-α-mediated reduction of PPARγ target genes [111]. Importantly, PPARγ is a key transcription factor of adipogenesis and is the target of the thiazolidinedione (TZD) class of anti-diabetic drugs [114].

Considering its lipid-lowering effects, quercetin was shown to play an important role in attenuating atherosclerosis via regulating reverse cholesterol transport (RCT) [115–118], via mechanisms that may also depend on its antioxidant effects [116]. Quercetin supplementation effectively up-regulates ATP-binding cassettes A1 and G1 (ABCAl and ABCG1), liver X receptor alpha (LXR-α) levels in RAW264.7 macrophages [118] and in atherosclerotic aortae [115], possibly via the activation of a p38-depedent pathway [119] (Figure 3). Quercetin also increases recruitment of LXR transcription factors to the promoter region of ABCA1and ABCG1 genes, promotes cholesterol efflux and attenuates foam cell formation [116]. It is important to note here that quercetin markedly increased cholesterol accepting ability of high-density lipoprotein (HDL) and apoA1, possibly by decreasing levels of plasma malondialdehyde (MDA) and oxidized phosphocholines in HDL [116]. Therefore, the antioxidant activity of quercetin may also contribute to the enhancement of cholesterol packaging into HDL and its delivery to the liver and excretion through the bile.

Another important anti-atherogenic effect of quercetin is its anti-proliferative action on VSMCs. In human aortic VSMCs, quercetin attenuated proliferation through G1 arrest via a reduction in ERK 1/2 activity [120]. In addition, quercetin down-regulated cyclins and cyclin-dependent kinases (CDKs), whereas it up-regulated CDK inhibitor protein 21 (p21) [120].

Overall, meta-analyses and RCTs involving quercetin have demonstrated contrasting results that may be attributed to the number of participants, variations in quercetin plasma concentrations and supplementation duration. A recent meta-analysis of 7 RCTs reported significant decreases in circulating CRP levels with quercetin doses > 500 mg/day in individuals with normal CRP levels [121]. Conversely, two other meta-analyses reported no significant effect of quercetin on other inflammatory markers such as IL-6 or TNF-α concentrations [122] or on plasma lipids (total-cholesterol, LDL-C, HDL-C, and TG) [123]. In another report in pre-hypertensive patients with a high body mass index, quercetin did not affect glucose, insulin, CRP, TNFα, leptin, or adiponectin levels. Importantly, in that study, researchers used a lower dose of 162 mg/d of quercetin for a total treatment period of 12 weeks indicating that the cardioprotective effects of quercetin on markers of inflammation may possibly require more time and higher dosing [124]. In fact, mean plasma concentration of quercetin in that study was 462 nmol/l [124] in contrast with plasma quercetin concentrations of >1 μM [111,125,126] or to high pharmacological dosages of >10 mg/kg body weight used in animal models [101,102]. In this regard, in women with Type 2 diabetes, 500 mg of quercetin for 10 weeks significantly decreased inflammatory markers, TNF-α and interleukin (IL-6) [127]. This inconsistency may also be explained through subject demographics where participant baseline co-morbidities are important factors to consider when crossing over from in vitro/in vivo studies into human studies. Overall, the above results suggest some form of threshold for cardioprotective bioactivity of quercetin through study population, dosage, and duration of treatment.

Kaempferol

Kaempferol, another important flavonol, has been associated with CVD risk reduction [128]. Although the detailed molecular mechanism of its protective effects on atherosclerosis are not fully understood, they appear to stem from kaempferol’s ability to act as an antioxidant.

In this regard, kaempferol was shown to effectively protect against lipid oxidation and endothelial dysfunction [129,130]. It is well document that endothelial cell (EC) injury and apoptosis are key early steps in the pathogenesis of atherosclerosis [131]. As a result, therapeutic strategies that prevent ox-LDL-induced endothelial dysfunction and apoptosis have received considerable attention in CVDs. In ox-LDL treated HUVECs, kaempferol reduced apoptosis and cellular ROS through increasing SOD activity and markedly restored oxLDL-induced viability loss [130] (Figure 2). Other studies demonstrated that kaempferol treatment improved endothelium-dependent vasorelaxation, increased NO plasma concentration, decreased asymmetric dimethylarginine (ADMA) and MDA plasma concentrations and increased the expression of aortic endothelial nitric oxide synthase (eNOS) and dimethylarginine dimethylaminohydrolase II (DDAH II) [130,132]. Another way in which kaempferol appears to alleviate ox-LDL-induced apoptosis in ECs is through modulation of mRNA [133] and autophagy [134]. In this regard, kaempferol up-regulated miR-26a-5p inactivating TLR4/NF-κB signaling which alleviated ox-LDL-induced apoptosis [133]. Another reported mechanism of reduced ox-LDL-induced apoptosis by kaempferol is via up-regulation of autophagy through phosphoinositide 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway inhibition [134].

Kaempferol treatment also appears to have favorable vascular and systemic anti-inflammatory effects. In high-cholesterol fed rabbits, kaempferol significantly reduced the expression of E-selectin, ICAM-1, VCAM-1, and MCP-1 in atherosclerotic aortas as well as decreased levels of TNF-α and IL-1β in serum [135] (Figure 2). This led to a pronounced reduction in the accumulation and transmigration of leukocytes as well as a reduction in atherosclerotic lesion size [2,135].

Macrophage-induced inflammation and adipocyte-macrophage interaction also has a primary importance in ATI [136]. It is also well known that large numbers of macrophages are recruited to adipose tissue via the actions of MCP-1, TNF-α, IL-1 β [137] which are down-regulated by kaempferol [135] (Figure 2). Thus, it is interesting to postulate that kaempferol may suppress ATI and improve metabolic status of adipocytes leading to cardioprotective benefits. In fact, a recent report demonstrated that exposure to kaempferol containing Arctomia borbonica extract in LPS-treated adipoctyes, decreased MCP-1 release, and increased the anti-inflammatory adiponectin release from these cells. Moreover, treatment of adipocytes with kaempferol decreased gene expressions of TLR2, TLR4, MyD88, and NF-κB [138].

Another cardioprotective benefit of kaempferol is due to a direct effect on lipogenesis and fatty acid oxidation signaling pathways through gene regulation. Specifically, kaempferol was shown to bind and activate PPARα with an affinity that was higher than fenofibrate, a known PPARα agonist. Activation of PPARα activity with kaempferol stimulated fatty acid oxidation signaling in adipocytes [139]. In high fat-fed mice, kaempferol treatment reduced body weight, adipose tissue and TG levels as well as improved insulin resistance and hyperlipidemia compared with the high fat-fed control group. These effects were attributed to down-regulation of PPARγ, C/EBPα, sterol regulatory element-binding protein 1 (SREBP-1c), and FAS indicating that kaempferol’s favorable effects on adipose tissue are due to its anti-adipogenic effects [139,140].

Similar to quercetin, kaempferol also appears to increase RCT from macrophages [141], an effect that is possibly attributable to an antioxidant activity. Kaempferol-induced increases in RCT from THP-1 macrophages were mediated via increases in ABCA1, ABCG1, and scavenger receptor class B type 1 (SR-BI) expression (Figure 4). This modulation was accompanied by increased protein expression of heme oxygenase-1 (HO-1) [141].

Overall, clinical trials on cardiovascular bioactivity of kaempferol are limited. The Nurses’ Health study observed a weak inverse association between kaempferol intake from food sources and risk of coronary heart disease [142]. These effects appear to be associated with anti-inflammatory properties for kaempferol. In that regard, a dose of >21.4 mg/day of kaempferol was significantly associated with lower IL-6 levels in individuals with inflammatory conditions [143].

Although this may appear promising, it is important to highlight that these studies were observational studies subject to recall bias. Moreover, intake of kaempferol in many studies is from food sources which introduces a number of issues. First, food sources contain other bioactive compounds that may contribute to or counteract the cardioprotective effects of kaempferol. Second, this leads to variations across studies and makes comparisons difficult. Interventional studies on kaempferol’s cardioprotective activities may benefit from the use of kaempferol supplements derived from plant sources. Due to the above, at this time, cardioprotective benefit of kaempferol is inconclusive and more extensive evidence is desperately needed to understand its cardiovascular effects in humans.

Flavanols

Flavanols are found in cocoa, tea, and cereals [144]. This class of flavonoids is known to oligomerize, at which point they are referred to as pro-anthocyanidins (otherwise known as reduced tannins) [144]. Here, the flavanols we review are ones known for their therapeutic effects against atherosclerosis and ATI. These include resveratrol, epicatechin (EC), epigallochatechin gallate (EGCG), and a few of their derivatives (where relevant). These effects are mediated by both antioxidant dependent and antioxidant independent pathways, both of which are summarized in proceeding tables.

Resveratrol (RE)

RE, or 3,5,4′ trihydoxystilbene, is a natural polyphenol that is found in many plants including tea, pomegranates and berries, and is highly concentrated in the skin of red grapes [145]. Accumulating evidence shows that RE has a bounty of therapeutic effects, such as being anti-inflammatory, antioxidant, anti-platelet, anti-hyperlipidemic, cardioprotective, and vasorelaxant, among others [145–150]. These effects endow RE with the potential capacity to favorably modulate ATI and atherosclerosis. Indeed, RE appears to ameliorate major risk factors of CVD by virtue of its ability to improve endothelial function, reduce inflammation, inhibit platelet aggregation, diminish levels of ROS, as well as favorably modulates lipidemic profile [151–153]. This is in addition to RE’s ability to preserve mitochondrial function, especially under hypoxia-induced oxidative stress [154]. The potential of RE to favorably modulate parameters of atherosclerosis is evident in its ability to ameliorate major hallmarks of this pathophysiologic condition. For instance, RE has been reported to reduce VSMC proliferation and promote autophagy [155], as well as inhibits calcification [156]. This is consistent with the very recent finding that RE inhibits intimal hyperplasia through a mechanism dependent on Nik-related kinase [157]. Moreover, RE’s protective effects on arterial aging have been shown to involve the renin–angiotensin system [158].

In the context of PVAT, it has been shown that PVAT-eNOS may play a far more important role in regulating vascular physiology than endothelial eNOS, at least under certain conditions [159]. Interestingly, a role for resveratrol in improving PVAT function has been reported [160,161]. For instance, acetylcholine-induced relaxation appears to be inhibited by conditioned media derived from animals that exhibit PVAT dysfunction [160,161]. In these animals, RE treatment was sufficient to elicit a significant reversal in PVAT dysfunction [160,161]. Others have also reported that RE plays a very important role in promoting a healthy adipose tissue, mostly by increasing expression of IL-10 and IL-13, thus suppressing local inflammation in the vicinity of this tissue [162]. This is in line with an earlier report showing that in adipocytes, RE reverses LPS-induced proteomic changes reminiscent of ATI [163].

Taken together, it is evident that RE exerts a therapeutic effect in the context of both atherosclerosis and ATI. This makes it a promising agent in the fight against these and other CVDs.

Epicatechin (EC)

Cocoa-derived EC was associated with acute and sustained increase in NO bioavailability in healthy adult males, which helped prevent endothelial dysfunction, counteracting a central event in atherogenesis [164]. In patients with peripheral artery disease, EC (and its epimer catechin) decreased activation of the vascular endothelium upon the co-incubation of HUVECs with activated platelets [165]. The mechanism underlying decreased activation involved phosphorylation of eNOS and consequent NO availability, accompanied by a decrease in soluble cell adhesion molecules (CAMs) [165]. These effects are envisioned to improve vascular function of cardiovascular patients. In addition, a randomized, placebo-controlled, crossover trial showed that EC administration to healthy men improved their endothelial function by increasing NO and decreasing ET-1 concentrations [166]. These effects are envisioned to improve vascular function of cardiovascular patients. By virtue of its free-radical scavenger ability NO quenches reactive oxygen species (ROS) such as superoxide by reacting with them, thereby reducing oxidative stress within the cell, and hence the risk of developing atherosclerosis.

Owing to its anti-inflammatory potential, EC attenuated atherosclerosis in a transgenic human-CRP mice strain and an NFκB-luciferase reporter mouse strain [167]. In ApoE*3-Leiden mice, EC decreased plaque lesion areas that were induced by high cholesterol diets [167]. This was accompanied by a reduction in the level of the inflammatory apolipoprotein serum amyloid A and a decrease in the number of neutrophils in plaque lesions [167]. Furthermore, EC attenuated chemotaxis and matrix remodeling in the aorta in the aforementioned mouse models [167]. These anti-inflammatory effects were mediated by inhibition of NF-κB which is not linked to the antioxidant pathway [167] (Figure 2). In Sprague-Dawley rats, gallic esters of ECs (such as (-)-Epicatechin 2-O-Gallate) demonstrated effective inhibition of the secretory sphingomyelinase (sSMase), a key enzyme involved in atherosclerosis [168]. Moreover, supplementing apo-E−/− mice strains with high EC-oligomer diet decreased the area of plaque deposits and reduced the levels of oxidative stress indicators such as LDL oxidation and foam cell formation [169]. Moreover, EC decreased ATI in high-fructose diet rats, mainly by up-regulating anti-inflammatory adipose hormones such as adiponectin or by decreasing pro-inflammatory cytokines [170]. Similar reduction of ATI was observed in EC-supplemented HFD-C57BL/6J mice [171]. This anti-inflammatory effect appears to be mediated by the down-regulation of several pro-inflammatory genes such as chemokine ligand 19 (CCL19) [172] and the decrease in levels of pro-inflammatory chemokines/cytokines NF-κB, TNF-α, and MCP-1 [171]. The decrease in these pro-inflammatory molecules was accompanied by a reduction in oxidative stress, mediated via the suppression of nicotinamide adenine dinucleotide phosphate oxidases (NOX) [171]. Although the NF-κB and TNF-α do not directly influence oxidative stress, NOX itself leads to the generation of ROS, which does increase the oxidative stress on the cell. The suppressive effect of the flavanol in turn decreases this stress and ameliorates the morbidity of atherosclerosis.

The studies reviewed herein span clinical trials (on human beings) and murine models derived from various well-documented strains. When taking a critical look at the differences and similarities between the results of the various in vivo studies, it may be noticed that EC has an anti-atherosclerotic and anti-inflammatory effect on both human and animal models. However, the difference lies in the mechanisms used to achieve this end. In the clinical trials, a NOS/antioxidant dependent pathway was observed. In regards to murine experiments, some pathways were entirely antioxidant independent (e.g. SMases and SAA), whilst others may have manifested themselves through both antioxidant dependent (i.e. involving NOX) and independent pathways (e.g. NF, TNF, IL, etc.)

Taken together, the above evidence reinforces the notion that EC possesses curative effect on atherosclerosis and ATI, and that is effect is achieved via the reduction of oxidative stress.

Epigallochatechin gallate (EGCG)

EGCG is another candidate flavanol for therapeutic use in treating atherosclerosis [144]. EGCG markedly decreased atherosclerotic plaque formation and levels of cytokines, IL-6 and TNF-α in ApoE-/- mice [173]. Dyslipidemia was also decreased, as evident by low LDL and total cholesterol content [173]. It has been suggested that such effects are mediated by the modulatory effect of EGCG on the LXR/SREBP-1 signaling pathway, which is involved in cholesterol metabolism in hepatic cells [173]. This pathway is not involved in the quenching/generation of free-radicals, and is hence antioxidant independent. Additionally, in HFD ApoE −/− mice, EGCG attenuated LDL oxidation via the Jagged-1/Notch cellular pathway [174]. Although the exact mechanism has of yet to be determined, it has been demonstrated that EGCG lowers levels of oxidized LDL, which in turn influenced levels of eNOS. Seeing as EGCG stabilizes levels of eNOS in HUVECs, this pathway may be considered ant-oxidant dependent, owing to the role of NO in scavenging for ROS. Furthermore, EGCC supplementation to Goto-Kakizaki rats decreased several pro-inflammatory proteins such as IL-18, TNF-α, MCP-1 and resistin with no established mechanism (besides the standard inflammatory pathway of cytokines) being established [175]. In HFD rats, EGCG decreased pro-inflammatory compounds such as interleukins, nuclear factors, and kinases [176]. In addition, EGCG down-regulated TLR-4, whose pathway directly leads the production of NF-κB, which is involved with ROS (making EGCG play an indirect antioxidant role) in adipose tissue [176]. In vitro, EGCG suppressed the TLR-4/MAPK/NF-κB signaling pathway in RAW264.7 macrophages, exhibiting atherosclerotic plaque stabilizing effects [177] (Figure 2). Seeing as the pathway found in this study mimicked that found in murine studies, the mechanisms are also the same. Knowing that TLR-4 signaling greatly mediates ATI [178], EGCG may present an important therapeutic potential against this disease. This is accomplished with EGCG by suppressing the TLR, which in turn decreases the amount of NF-κB, a potent transcription factor for enzymes which increase ROS, such as COX-2.

In the context of ATI, little is known about EGCG. However, EGCG–resveratrol combination was shown to cause the down-regulation of several pathways integral to oxidative stress, immune activation, and inflammation in obese individuals, in comparison to the placebo control [179]. As such, it would be reasonable to hypothesize that EGCG contributes to the attenuation of ATI. However, this remains to be established. It remains to be demonstrated by which pathway such effects are brought about.

When surveying the results of the aforementioned studies under a critical lens, it is unfortunate to note that only in vivo murine studies were used and compared to in vitro studies on macrophages. The lack of literature on the effect of EGCG in clinical studies serves as an area where further research could prove effective. However, it was shown that EGCG acutely improves endothelial function in humans with coronary artery disease [180]. Knowing that improving endothelial function alleviates atherosclerosis, it would be interesting to assess the anti-atherogenic potential of EGCG in a randomized clinical trial [166].

In regards to the studies covered, common patterns were observed, implicating the ubiquity of cytokines (e.g. interleukins, chemokines, necrosis factors, nuclear factors) and toll-like receptors in the inflammatory and atherosclerotic response. While many factors did eventually lead to an increase in ROS, which increases oxidative stress and risk for development of CVDs, not all pathways were dependent of their oxidative effects.

Flavanones

Flavanones are found in citrus fruits and tomatoes, in addition to mint and cumin [181]. They are associated with a reduced risk of CVD [182], probably due to their strong antioxidant activity. Flavanones include naringenin, narirutin, liquoritigenin, naringin, sterubin, sakuranin, eriodictyol, hesperetin, neohesperidin, and hesperidin [181].

Hesperidin/Hesperetin

Overwhelming evidence support the antioxidative potential of hesperidin/hesperetin. For instance, hesperidin inhibited oxidative stress and inflammation by enhancing enzymatic and non-enzymatic antioxidant defenses, in addition to down-regulating NF-κB and iNOS mRNA expression [183]. Hesperidin also attenuated ROS, NO, and lipid peroxides via Nrf2/antioxidant response element (ARE)/HO-1 signaling pathway [184]. Likewise, hesperitin, the aglycone of hesperidin, increased the activity of antioxidant enzymes SOD, CAT, and GPx, and decreased lipid peroxidation [185]. Owing to this antioxative capacity, hesperidin and hesperitn are thought to have atherogenic and anti-inflammatory potential. However, other antioxidant-independent effects of these flavanones also contribute to their vasculoprotective effects.

Clinical trials showed that hesperidin decreased cholesterol and ApoB levels in patients with metabolic diseases [186]. In addition, hesperidin regulated the expression of 1819 genes in leukocytes of healthy individuals. Most of the altered genes play a role in chemotaxis, adhesion, infiltration, and lipid transport [187]. Therefore, hesperidin may potentially inhibit macrophage infiltration and lipid accumulating, key events in atherosclerosis and ATI.

Hesperidin and its aglycone, hesperetin, are reported to play an anti-atherogenic role by decreasing plasma cholesterol levels in apo-E−/− mice [188]. In addition, both flavanones attenuated atherosclerotic lesion by reducing plaque formation, adipose deposition, and macrophage infiltration [188]. Hesperidin would be expected to ameliorate ATI owing to its potential in reducing foam cell formation, weight gain, and hyperlipidemia in HFD-ldlr−/− mice [189]. Indeed, these effects are attributed to hesperidin-induced regulation of hepatic enzymes involved in fatty acid/triglyceride synthesis; and transporters ABCG8, ABCA1 and ABCG1 involved in reverse cholesterol transport [189] (Figure 4). This beneficial role of hesperetin in ATI was further confirmed by another study reporting that the addition of 1% hesperetin to orotic acid-supplemented rats decreased hepatic cholesterol and triglyceride [190]. These hesperetin-induced effects were mediated via attenuating hepatic microsomal phosphatidate phosphohydrolase (PAP) [190]. In addition, hesperetin diminished plasma cholesterol in cholesterol-diet rats by down-regulating key enzymes involved in cholesterol synthesis and transport [191]. These enzymes include hepatic 3-hydroxy-3-methylglutaryl-Coenzyme A (HMG-CoA) reductase and acyl-CoA cholesterol acyltransferase (ACAT) [191].

In vitro, hesperetin attenuated platelet aggregation by inhibiting phosphatidylinositol-4,5-isphosphate phosphodiesterase gamma-2 (PLC- γ2) and cyclooxygenase-1 (COX-1) activity [192]. In addition to this anti-atherogenic effect, hesperetin is assumed to have a modulatory effect on ATI by reducing apoB secretion and cholesteryl ester synthesis in HepG2 [193].

Hesperidin/hesperitin decreased ApoB levels in human subjects and in vitro [186,193]. In Addition, hesperidin/hesperitin down-regulated genes involved in lipid transport [187]. Similar results were obtained in vivo, where hesperidin/hesperitin attenuated HMG-CoA reductase and ACAT, both enzymes play a role in cholesterol synthesis and transfer [191].

Naringin/Naringenin

Naringin and Naringenin are characterized by antioxidant potential, as evident by their capacity to scavenge hydroxyl and superoxide radicals [194]. This effect was mediated by attenuating the enzyme xanthine oxidase. In addition, both flavanones were also efficient in protect against lipid peroxidation and DNA cleavage [194]. This antioxidant effect was translated in naringenin-administered human subjects by enhancement of detoxifying enzymes [195].

Clinically, while naringenin decreased serum LDL-C, cholesterol and ApoB levels and increased HDL-C levels in hypercholesterolemic patients [196], a higher dose of naringin did not affect lipid profile in patients with moderate hypercholesterolemia [195].

Naringin, by virtue of its antioxidative capacity, plays a key role in inhibiting lipid peroxidation in cholesterol-fed rabbits [197]. The naringin-provoked antioxidative effect is mediated via the up-regulation of SOD, glutathione peroxidase (GSH-Px) and catalase transcripts, and increased activity of hepatic SOD and catalase [197] (Figure 2). In addition, supplementation of HFD rats with naringenin decreased hepatic and plasma cholesterol and hepatic TAG. This decrease in cholesterol and TAG was concomitant with reduced activity of HMG-CoA reductase and ACAT [198,199]. As such, it is reasonable to postulate that both naringin and naringenin may be used as a curative agent to ATI.

It is noteworthy that despite LDL-cholesterol lowering effect of naringin in rodent models [200], naringin failed to lessen serum cholesterol levels in hypercholesterolemic human subjects [201].

Anthocyanins

Anthocyanins are phenolic pigments responsible for the red, blue, and purple color of fruits (berries, currants, and grapes) and vegetables (black carrot, red cabbage, and purple potato) [202]. Importantly, anthocyanin-containing flowers are used in folk medicine to treat CVD [202]. Indeed, clinical evidence supports the notion that anthocyanin intake is associated with reduced cardiovascular risk [203].

Overwhelming evidence support the antioxidant capacity of anthocyanins [204]. Anthocyanins trap peroxyl radicals, thus protecting cell membrane from peroxidation. The antioxidant capacity of anthocyanins was also documented by oxygen radical absorbance capacity (ORAC) method [205] and by ABTS method [206]. Both methods showed that anthocyanins have at least two times higher antioxidant potential than trolox (a synthetic antioxidant).

In accordance with these studies, anthocyanins were reported to increase serum antioxidant capacity in human subjects [207], and reduce ROS production in mice aorta [208]. Owing to this antioxidant potential, anthocyanins were anticipated to have anti-atherogenic capacity. Other antioxidant independent effects of anthocyanins have been also documented (Table 2). For instance, serum CRP, which contributes to atherosclerotic plaque instability [209], is inversely associated with anthocyanin consumption in humans [207]. In addition, anthocyanin consumption increased serum antioxidant capacity [210], reduced serum cholesterol/triglycerides and decreased the number of activated platelets [211]. Adults supplemented with anthocyanin showed decreased serum pro-inflammatory inducers of NF-κB, such as IL-13, 8, 4, 2 and interferon alpha (IFNα) [212] (Figure 2). Importantly, pro-inflammatory cytokines such as IL-1β, IL-6, CRP, and TNF-α are produced in adipocytes [213] and their expression is increased in obese individuals [214]. Thus, targeting these cytokines by anthocyanins would only be expected to reduce ATI as well.

Table 2
Antioxidant dependent and antioxidant independent effects of flavonoids
FlavonoidAntioxidant dependentAntioxidant independent
Luteolin In vivo ↑ Serum SOD and NO In atherosclerotic rats, ↓ ICAM-1 and VCAM-1 
   ↓TNF-α, IL-6, and CRP 
   ↓ HFD rats and ldlr-/- mice, serum levels of cholesterol, triglyceride and LDL 
 In vitro  Inhibition of VSMC proliferation and migration by down-regulating Akt and Src and abolishing NF-κB translocation 
   Attenuation of cell adhesion by suppression of endothelial ICAM-1 and VCAM-1 
   In macrophages, p38-mediated TNF-α and IL-6 expression 
Nobiletin In vivo  In ldlr -/- mice and in C57BL/6J mice, β-oxidation, ↓ VLDL-TG, and cholesterol 
   ↓ Number and the size of fat droplets in liver 
   Phosphorylation of hepatic AMPK and its downstream target acetyl-coenzyme carboxylase (ACC) 
   ↓ NF‐κB, TNF‐α, TLR2, and TLR4 
   ↑ FA oxidation genes, PPARα, and CPT1a 
 In vitro  ↑ In HepG2 cells, DGAT1, and DGAT2 
   Inhibition of ApoB-100 secretion 
   ERK1/2 activation 
   In macrophages, inhibition of class A scavenger receptor-mediated metabolism of acetylated LDL 
Tangeretin In humans  ↓ Serum cholesterol and TG 
 In vivo  ↓ Body weight and plasma lipids of diabetic rats 
   ↓ Cardiac lipid peroxidation 
   ↓ Serum TNF-α, IL-6, CRP, and NF-κB 
 In vitro  In HepG2 cells, ↓ ApoB secretion, cholesterol synthesis, TAG synthesis, and lipid metabolism 
 In vitro  ↓ Activity of DAG acyltransferase and microsomal triglyceride transfer protein 
   In 3T3-L1 adipocytes, ↓ lipid and triglyceride accumulation 
   ↓ Thrombus formation 
   ↓ Platelet activation and aggregation 
   Inhibition of integrin αIIbβ3 
   ↑ cGMP and levels ↓ Akt phosphorylation 
Quercetin In vivo ↓NF-κB activation through suppression of ROS overproduction In ApoE-/- mice, ↓ Src/Akt/NF- κB signaling and ↓ IL‐6, IL‐12, CD80, CD86, MHC‐II 
   In ApoE-/- mice ↓ atherosclerotic lesion size 
   In C5BL/6J mice, ↓ IFNγ TNFα, IL-1, and IL-4 
   In C5BL/6J mice, ↓ lipid deposition, macrophage and T cell infiltration in atherosclerotic lesions 
   In ApoE-/- mice, ↓ expressions of ABCA1, LXR- α and PCSK9 in atherosclerotic aortas 
   In ApoE-/- mice, ↑ cholesterol efflux, cholesterol accepting ability of HDL and apoA1 and ↓ foam cell formation possibly through ↓ MDA and oxidized phosphocholine levels in HDL 
 In vitro In ox-LDL treated HUVECs), ↓ expression of VCAM-1 and ICAM-1 by decreasing activation of the TLR-NF-κB signaling ↓ Inflammatory gene expression and capacity of U937 macrophages infiltrate into adipose tissue and inflame adipocytes 
  In ox-LDL treated RAW264.7 macrophages, ↑ ABCAl, ABCG1 and LXR-α levels In 3T3-L1 preadipocytes, ↓ adipogenesis through ↓ (C/EBP α) mRNA levels, and ↓ lipogenesis through ↓ the gene levels of FAS and ACC 
   In 3T3-L1 preadipocytes, ↑ Apoptosis via ERK and c-jun-N-terminal kinase (JNK) pathways 
   Inhibition of TNF-α-mediated reduction of PPARγ target genes 
   In human aortic VSMCs, ↓ proliferation through ↓ ERK 1/2 activity and ↑ p21 
Kaempferol In vivo In ApoE-/- mice, ↑ endothelium-dependent vasorelaxation, ↑ plasma NO, eNOS, DDAH II espression and ↓ ADMA and MDA plasma concentrations In high fat-fed mice, ↑ body weight and TG levels and improved insulin resistance and hyperlipidemia due to ↓ of PPARγ and SREBP-1c 
  In high-cholesterol fed rabbits, ↓ E-selectin, ICAM-1, VCAM-1 and MCP-1 in atherosclerotic aortas and ↓ TNF-α and IL-1β in serum  
 In vitro In ox-LDL treated HUVECs, ↓ apoptosis and cellular ROS, ↑ SOD activity In human aortic endothelial cells, ↑ miR-26a-5p inactivating TLR4/NF-κB signaling and ↓ apoptosis 
  ↑ RCT from THP-1 macrophages through ↑ in ABCA1, ABCG1, SR-BI and HO-1 expression In ox-LDL treated HUVECS, ↓ apoptosis via inhibition of PI3K/Akt/mTOR pathway 
   In LPS-treated adipoctyes, ↓ MCP-1, ↑ adiponectin release and ↑ gene expressions of TLR2, TLR4, MyD88 and NFκB 
   ↑ PPARα activity and ↑ fatty acid oxidation signaling in adipocytes 
Epicatechin In humans ↑ eNOS phosphorylation ↓ Soluble CAM 
  ↑ NO bioavailability  
  ↓ Activation of the vascular endothelium  
 In vivo In apo-E-/- mice, ↓ oxidative stress indicators such as LDL oxidation and foam cell formation In ApoE*3-Leiden mice, ↓ serum amyloid A and neutrophils
Inhibition of NF-κB 
  In HFD-C57BL/6J mice, suppression of NOX Inhibition of sSMase 
   In high-fructose diet rats, ↑ adiponectin 
   ↓ Pro-inflammatory cytokines 
   In HFD-C57BL/6J mice, ↓ CCL19, NF-κB, TNF-α, and MCP-1 
Epigallocatechin In vivo  In ApoE-/- mice, ↓ IL-6 and TNF-α 
   ↓ LDL and total cholesterol 
   ↓ LXR/SREBP-1 signaling pathway 
   In HFD ApoE-/- mice, attenuation of LDL oxidation via the Jagged-1/Notch cellular pathway 
   In Goto-Kakizaki rats, ↓ IL-18, TNF-α, MCP-1, and resistin 
   In HFD rats, ↓TLR-4 
 In vitro Stabilization of eNOS in HUVECs Suppression of the TLR4/MAPK/NF-κB signaling pathway in RAW264.7 macrophages 
Anthocyanin In humans ↑ Serum antioxidant capacity ↓ Serum cholesterol/triglycerides 
   ↓ Activated platelets 
   ↓ IL-13, 8, 4, 2, and IFNα 
 In vivo ↓ ROS production in mice aorta In HFD mice, ↓ lipid accumulation and body weight 
   ↓ Serum cholesterol, triglycerides, and leptin 
   In ApoE-/- mice, ↓ serum and macrophage TNF-α and IL-6 
   Inhibition of IκB, NF-κB, p38 and JNK 
 In vitro  ↓ Platelet activation and aggregation 
   ↓ P-selectin 
   Inhibition of NF-κB activation and MAPK in monocytes 
Hesperidin/Hesperetin In vivo  In apo-E-/- mice, ↓ plasma cholesterol 
   In HFD-ldlr-/- mice, regulation of ABCG8, ABCA1, and ABCG1 
   ↓ Hepatic microsomal phosphatidate phosphohydrolase (PAP) 
   Down-regulation of hepatic HMG-CoA reductase and ACAT 
 On vitro Inhibition of COX-1 in platelet Inhibition of PLC- γ2 in platelet 
   ↓ ApoB secretion and cholesteryl ester synthesis in HepG2 
Naringin/Naringenin In vivo In cholesterol-fed rabbits, ↑ SOD, GSH-Px, and catalase transcripts ↓ HMG-CoA reductase and ACAT 
Isoflavones In vivo In SHR aortas, improved endothelial cell function and ↑ acetylcholine-mediated relaxation via ↑ in eNOS activity and ↓ superoxide production  
  ↓ iNOS and NO accompanied by ↓ NF-ĸB, TNF-α and IL-1β in male wistar rats (genistein)  
 In vitro Inhibition of ox-LDL induced eNOS uncoupling through ↑ of HO-1 and Nrf2 in HUVECs (genistein) In Male CD-1 mice, ↑ transfer of triglycerides to the liver by ↑ AMPK activity 
  ↑ Sirtuin-1 dependent down-regulation NOX 4 expression in ox-LDL treated HUVECs (genistein) ↑ Apoptosis of mature adipocytes via AMPK activation (genistein) 
   Anti-adipogenic effects through ↑ of ER-dependent Wnt signaling 
FlavonoidAntioxidant dependentAntioxidant independent
Luteolin In vivo ↑ Serum SOD and NO In atherosclerotic rats, ↓ ICAM-1 and VCAM-1 
   ↓TNF-α, IL-6, and CRP 
   ↓ HFD rats and ldlr-/- mice, serum levels of cholesterol, triglyceride and LDL 
 In vitro  Inhibition of VSMC proliferation and migration by down-regulating Akt and Src and abolishing NF-κB translocation 
   Attenuation of cell adhesion by suppression of endothelial ICAM-1 and VCAM-1 
   In macrophages, p38-mediated TNF-α and IL-6 expression 
Nobiletin In vivo  In ldlr -/- mice and in C57BL/6J mice, β-oxidation, ↓ VLDL-TG, and cholesterol 
   ↓ Number and the size of fat droplets in liver 
   Phosphorylation of hepatic AMPK and its downstream target acetyl-coenzyme carboxylase (ACC) 
   ↓ NF‐κB, TNF‐α, TLR2, and TLR4 
   ↑ FA oxidation genes, PPARα, and CPT1a 
 In vitro  ↑ In HepG2 cells, DGAT1, and DGAT2 
   Inhibition of ApoB-100 secretion 
   ERK1/2 activation 
   In macrophages, inhibition of class A scavenger receptor-mediated metabolism of acetylated LDL 
Tangeretin In humans  ↓ Serum cholesterol and TG 
 In vivo  ↓ Body weight and plasma lipids of diabetic rats 
   ↓ Cardiac lipid peroxidation 
   ↓ Serum TNF-α, IL-6, CRP, and NF-κB 
 In vitro  In HepG2 cells, ↓ ApoB secretion, cholesterol synthesis, TAG synthesis, and lipid metabolism 
 In vitro  ↓ Activity of DAG acyltransferase and microsomal triglyceride transfer protein 
   In 3T3-L1 adipocytes, ↓ lipid and triglyceride accumulation 
   ↓ Thrombus formation 
   ↓ Platelet activation and aggregation 
   Inhibition of integrin αIIbβ3 
   ↑ cGMP and levels ↓ Akt phosphorylation 
Quercetin In vivo ↓NF-κB activation through suppression of ROS overproduction In ApoE-/- mice, ↓ Src/Akt/NF- κB signaling and ↓ IL‐6, IL‐12, CD80, CD86, MHC‐II 
   In ApoE-/- mice ↓ atherosclerotic lesion size 
   In C5BL/6J mice, ↓ IFNγ TNFα, IL-1, and IL-4 
   In C5BL/6J mice, ↓ lipid deposition, macrophage and T cell infiltration in atherosclerotic lesions 
   In ApoE-/- mice, ↓ expressions of ABCA1, LXR- α and PCSK9 in atherosclerotic aortas 
   In ApoE-/- mice, ↑ cholesterol efflux, cholesterol accepting ability of HDL and apoA1 and ↓ foam cell formation possibly through ↓ MDA and oxidized phosphocholine levels in HDL 
 In vitro In ox-LDL treated HUVECs), ↓ expression of VCAM-1 and ICAM-1 by decreasing activation of the TLR-NF-κB signaling ↓ Inflammatory gene expression and capacity of U937 macrophages infiltrate into adipose tissue and inflame adipocytes 
  In ox-LDL treated RAW264.7 macrophages, ↑ ABCAl, ABCG1 and LXR-α levels In 3T3-L1 preadipocytes, ↓ adipogenesis through ↓ (C/EBP α) mRNA levels, and ↓ lipogenesis through ↓ the gene levels of FAS and ACC 
   In 3T3-L1 preadipocytes, ↑ Apoptosis via ERK and c-jun-N-terminal kinase (JNK) pathways 
   Inhibition of TNF-α-mediated reduction of PPARγ target genes 
   In human aortic VSMCs, ↓ proliferation through ↓ ERK 1/2 activity and ↑ p21 
Kaempferol In vivo In ApoE-/- mice, ↑ endothelium-dependent vasorelaxation, ↑ plasma NO, eNOS, DDAH II espression and ↓ ADMA and MDA plasma concentrations In high fat-fed mice, ↑ body weight and TG levels and improved insulin resistance and hyperlipidemia due to ↓ of PPARγ and SREBP-1c 
  In high-cholesterol fed rabbits, ↓ E-selectin, ICAM-1, VCAM-1 and MCP-1 in atherosclerotic aortas and ↓ TNF-α and IL-1β in serum  
 In vitro In ox-LDL treated HUVECs, ↓ apoptosis and cellular ROS, ↑ SOD activity In human aortic endothelial cells, ↑ miR-26a-5p inactivating TLR4/NF-κB signaling and ↓ apoptosis 
  ↑ RCT from THP-1 macrophages through ↑ in ABCA1, ABCG1, SR-BI and HO-1 expression In ox-LDL treated HUVECS, ↓ apoptosis via inhibition of PI3K/Akt/mTOR pathway 
   In LPS-treated adipoctyes, ↓ MCP-1, ↑ adiponectin release and ↑ gene expressions of TLR2, TLR4, MyD88 and NFκB 
   ↑ PPARα activity and ↑ fatty acid oxidation signaling in adipocytes 
Epicatechin In humans ↑ eNOS phosphorylation ↓ Soluble CAM 
  ↑ NO bioavailability  
  ↓ Activation of the vascular endothelium  
 In vivo In apo-E-/- mice, ↓ oxidative stress indicators such as LDL oxidation and foam cell formation In ApoE*3-Leiden mice, ↓ serum amyloid A and neutrophils
Inhibition of NF-κB 
  In HFD-C57BL/6J mice, suppression of NOX Inhibition of sSMase 
   In high-fructose diet rats, ↑ adiponectin 
   ↓ Pro-inflammatory cytokines 
   In HFD-C57BL/6J mice, ↓ CCL19, NF-κB, TNF-α, and MCP-1 
Epigallocatechin In vivo  In ApoE-/- mice, ↓ IL-6 and TNF-α 
   ↓ LDL and total cholesterol 
   ↓ LXR/SREBP-1 signaling pathway 
   In HFD ApoE-/- mice, attenuation of LDL oxidation via the Jagged-1/Notch cellular pathway 
   In Goto-Kakizaki rats, ↓ IL-18, TNF-α, MCP-1, and resistin 
   In HFD rats, ↓TLR-4 
 In vitro Stabilization of eNOS in HUVECs Suppression of the TLR4/MAPK/NF-κB signaling pathway in RAW264.7 macrophages 
Anthocyanin In humans ↑ Serum antioxidant capacity ↓ Serum cholesterol/triglycerides 
   ↓ Activated platelets 
   ↓ IL-13, 8, 4, 2, and IFNα 
 In vivo ↓ ROS production in mice aorta In HFD mice, ↓ lipid accumulation and body weight 
   ↓ Serum cholesterol, triglycerides, and leptin 
   In ApoE-/- mice, ↓ serum and macrophage TNF-α and IL-6 
   Inhibition of IκB, NF-κB, p38 and JNK 
 In vitro  ↓ Platelet activation and aggregation 
   ↓ P-selectin 
   Inhibition of NF-κB activation and MAPK in monocytes 
Hesperidin/Hesperetin In vivo  In apo-E-/- mice, ↓ plasma cholesterol 
   In HFD-ldlr-/- mice, regulation of ABCG8, ABCA1, and ABCG1 
   ↓ Hepatic microsomal phosphatidate phosphohydrolase (PAP) 
   Down-regulation of hepatic HMG-CoA reductase and ACAT 
 On vitro Inhibition of COX-1 in platelet Inhibition of PLC- γ2 in platelet 
   ↓ ApoB secretion and cholesteryl ester synthesis in HepG2 
Naringin/Naringenin In vivo In cholesterol-fed rabbits, ↑ SOD, GSH-Px, and catalase transcripts ↓ HMG-CoA reductase and ACAT 
Isoflavones In vivo In SHR aortas, improved endothelial cell function and ↑ acetylcholine-mediated relaxation via ↑ in eNOS activity and ↓ superoxide production  
  ↓ iNOS and NO accompanied by ↓ NF-ĸB, TNF-α and IL-1β in male wistar rats (genistein)  
 In vitro Inhibition of ox-LDL induced eNOS uncoupling through ↑ of HO-1 and Nrf2 in HUVECs (genistein) In Male CD-1 mice, ↑ transfer of triglycerides to the liver by ↑ AMPK activity 
  ↑ Sirtuin-1 dependent down-regulation NOX 4 expression in ox-LDL treated HUVECs (genistein) ↑ Apoptosis of mature adipocytes via AMPK activation (genistein) 
   Anti-adipogenic effects through ↑ of ER-dependent Wnt signaling 

A substantial number of in vivo reports corroborated the capacity of anthocyanins in ameliorating atherosclerosis and ATI. For instance, the anthocyanin fraction of boysenberry reduced ROS production in mice aorta [208]. This antioxidant effect greatly ameliorated atherosclerotic lesion by maintaining vascular homeostasis and mitigating ROS-mediated inflammatory reactions [184,185,193,196,201,206,208,213,215,]. In addition, anthocyanin consumption decreased lipid accumulation and body weight in HFD mice [216–218]. This decrease was concomitant with a decline in the levels of serum cholesterol, triglycerides, and leptin [215], therefore alleviating ATI. In ApoE−/− mice, anthocyanin-rich blueberries decreased serum and macrophage pro-inflammatory cytokines TNF-α and IL-6. This effect appeared to be mediated by the inhibition of inhibitor of kappa B (IκB), NF-κB, p38, and JNK [219].

Anthocyanins provoked similar anti-inflammatory effects in vitro. For example, anthocyanins decreased platelet activation and aggregation [211]. This anti-thrombotic activity was elicited via decreasing P-selectin expression [220]. Furthermore, anthocyanin inhibited NF-κB activation in cultured monocytes [212]. This anthocyanin-induced attenuation of NF-κB was mediated by MAPKs inhibition [221]. Therefore, it is only reasonable to hypothesize that anthocyanins elicit alleviate atherosclerosis and ATI by MAPKs inhibition.

Collectively, these studies show that anthocyanins elicit their anti-atherosclerotic and anti-inflammatory effects by activating or inhibiting certain molecular pathways that may overlap in different models. For instance, anhocyanins attenuated NF-κB and MAPK activation and in cultured monocytes. This result was mirrored in vivo, namely in macrophages of ApoE−/− mice [222,223]. Furthermore, anthocyanins attenuated platelet activation in vitro and in human subjects [211]. Importantly, anthocyanin-induced decrease of pro-inflammatory cytokines was observed in vivo as well as in clinical trials [222,224]. In addition, serum cholesterol and triglycerides was diminished in both models in response to anthocyanins. Therefore, the in vitro and in vivo beneficial effects of anthocyanins are also observed in humans. These promising results prompt the scientific community to conduct more clinical research to determine the optimal daily dosage of anthocyanin for healthy as well as atherosclerotic individuals, and to dissect the molecular mechanisms underlying prevention and treatment, respectively.

Isoflavones

Isoflavones belong to a class of estrogen-like molecules that are structurally similar to 17β-estradiol [225], with a controversial connotation as being agonists of estrogen receptors [226]. The role of estrogen in the cardiovasculature, particularly in CVD, has already been published [227–231]. The two main isoflavones are genistein and daidzein, commonly found in soy products such as soy beans, soy dairy substitutes and soy meat substitutes [232].

Genistein and daidzein

Several animal/cell culture studies and some clinical trials have suggested a protective effect of isoflavones against atherosclerosis through improvement of endothelial cell function, metabolic profile, and inflammation [233–236]. Due to their antioxidant effects, both genistein and daidzein, improved endothelial cell function and enhanced acetylcholine-mediated relaxation in aortas in spontaneous hypertensive rats [237]. This relaxation was mediated via an increase in eNOS activity and a reduction of NOX-induced superoxide production [237] (Figure 2). Similar results were noted in vitro, as genistein inhibited ox-LDL–induced eNOS uncoupling in endothelial cells through up-regulation of HO-1, its transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) [238] and sirtuin-1 dependent down-regulation of nicotinamide adenine dinucleotide phosphate oxidase 4 (NOX 4) expression [239].

As mentioned earlier, an important anti-atherosclerotic property of isoflavones pertains to their ability to modulate the inflammatory response. In this respect, several cell culture and animal studies have reported that these compounds can down-regulate a number of inflammatory mediators including TNF-α and IL-6 in different cell lines [240,241]. Since ATI is also mediated by these factors, it is possible that dietary isoflavones can improve insulin sensitivity and atherogenesis at least in part through alleviation of ATI [242,243].

Several lines of evidence have demonstrated that isoflavones can regulate lipid metabolism in adipocytes, leading to the reduction of body weight, plasma lipid levels, and visceral fat area [244–246]. Other reports have indicated that isoflavone metabolites, S-equol and O-desmethylangolensin (O-DMA), and could regulate various transcription factors such as PPARα, PPARβ, and PPARγ [247]. Specifically, genistein limits adipocyte fat accumulation through the up-regulation of PPARα, AMPK and very long-chain acyl CoA dehydrogenase (VLCAD) genes and the down-regulation of genes associated with adipogenesis, such as LXR, SREBP1c, PPARγ, and ACC [248]. Of these, AMPK is particularly important as it is a key regulator of cellular and systemic energy balance and is considered to play an important role in the metabolism of adipose tissue [249,250]. In this respect, isoflavones were shown to promote the transfer of triglycerides to the liver by increasing AMPK activity [251], and Genistein was shown to stimulate apoptosis of mature adipocytes via AMPK activation [252].

Another interesting feature of this class of flavonoids with respect to ATI stems from their estrogen-like effects. These compounds share structural similarities with steroid hormones and can interact with estrogen receptors (ER) [98]. ERs exhibit bidirectional crosstalk with PPARγ [253]. Indeed, genistein and daizein exert anti-adipogenic effects through activation of ER-dependent Wnt signaling [254]. Taken together, evidence points toward the potential use of isoflavones to remediate atherosclerosis and reduce ATI.

Some human studies on isoflavones have reported important cardioprotective effects [234,255–258]. However, results have not been consistent [259,260], and the mechanisms by which isoflavones exert their effects still remain unclear. This inconsistency can be explained through a number of factors including isoflavone content, genetics, lifestyle and most notably, menopausal status [261].

As mentioned earlier, an important compound with cardioprotective activity related to isoflavones is S-equol [234,262]. However, isoflavone metabolism differs across populations. For, example, in western countries, less than 50% of individuals appear to be equol producers [234]. It is also known that postmenopausal women have a much lower or an inability to produce equol [263]. In this regard, a report in women aged 45–92 demonstrated that only in the subgroup of women within 5 years of menopause, isoflavone consumption led significant reduction in subclinical atherosclerosis. Another study demonstrated that in women at early menopause, soy isoflavone supplementation for 2.7 years reduced systolic blood pressure and cardiovascular risk markers such as 10 year coronary heart disease risk, myocardial infarction risk, cardiovascular disease and cardiovascular disease death risk [234]. Other studies in postmenopausal women reported a weaker effect of isoflavones in this population [260,263]. We have recently published on a novel homoisoflavonoid that appears to inhibit phenotypic switch in vascular smooth muscles of human arterioles [264]. Overall, isoflavones appear to have beneficial bioactivity that may endorses their use in a number of inflammatory diseases including atherosclerosis. However, rigorous human studies are still necessary to fully understand their underlying mechanisms of action and to bridge data between the in vitro/in vivo studies and the clinical trials.

The antioxidant-dependent and antioxidant-independent effects of flavonoids are summarized in Table 2.

Conclusions and safety remarks

Prevention of CVD presents itself as one of the greatest medical challenges globally. CVD continues to be associated with significant morbidity and mortality, with the vast majority of CVD being associated with atherosclerosis [265]. As such, tools for prevention and treatment of atherosclerosis are a milestone in decreasing CVD-related mortality. As the pathogenesis of atherosclerosis includes a crucial inflammatory component, an increase in adipose tissue plays a critical role in the precipitation and progression of the disease [10]. ATI results in enhanced macrophage recruitment, adipokine secretion, insulin resistance as well as lipid and metabolic profile impairment, all of which contribute to more aggressive vascular complications [10,11].

Currently, multiple epidemiological studies have shown an overall inverse relation between consumption of flavonoids and CVD mortality and risk. Due to their potential in the prevention of atherosclerosis, flavonoids have generated massive therapeutic interest as future pharmacological agents [266]. Although flavonoids are generally considered safe, it is important to consider the study population and inter-individual variation. Moreover, it is crucial to note that toxicity and drug interactions with flavonoids are considerably understudied topics [45]. This may be especially important in elderly subjects, as they are high risk individuals who more susceptible to these concerns. Notably, it has been reported that high flavonoids composition can lead to thyroid toxicity and carcinogenesis [267,268]. Moreover, out of the flavonoids studied, resveratrol and kaempferol are inhibitors of human cytochrome P450 1A1 (CYP1A1) [269]. Hence, modifying the efficacy of many drugs that are metabolized via a CYP1A1-dependent pathway is of clinical relevance [226].

Although the above data generally supports the recommendation of plant-based diets, there are many concerns surrounding future trials which will be discussed below. If flavonoids are to be recommended as future preventative/therapeutic treatment options, future studies should be targeted at exploring individual flavonoid effects and understanding their dose–response relationships. To do this, determination of exact content of individual flavonoids consumed from flavonoid rich foods is crucial [270]. Moreover, trials should employ a critical evaluation of dietary background for other flavonoid content and/or for possible interactions with different foods. This is important because one of the major challenges in nutraceutical research is identifying whether favorable effects are a result of an individual’s overall diet, or they are attributable to a specific compound [271]. It is also important from a pharmacokinetic perspective as the relative bio-availabilities of different flavonoid compounds could be altered by ingestion of other nutrients or medications [272]. A possible strategy would be to use a pre-specified washout diet before study initiation to ascertain that dietary flavonoid supply is within a specified range. Moreover, investigators’ characterization of background dietary habits may set an important foundation for data stratification or subject randomization. For example, it would be important to identify individuals with an atypical consumption of flavonoids like vegans or vegetarians [273]. Although challenging, the above factors are important because it allows researchers to understand results in the context of total dietary flavonoid intake and allows for easier comparisons across trials and establishment of dose–response relationships

Another major challenge surrounding clinical trials is due to the nature of the disease itself. Atherosclerosis it a complex multifactorial disease, and so it has been difficult to design clinical trials to find a treatment or a cure [274]. Currently, treatment consists of prevention/slowing down progression through improvement of metabolic status and management of risk factors [274]. In short, there is no single target or straight forward approach to atherosclerosis treatment. As a result, clinical trials have mainly focused on estimated serum indicators as relevant surrogate markers of atherosclerosis and CVD risk or CVD-related mortality [261]. There is no robust evidence on the direct effect of flavonoids on atherosclerosis. The growth new imaging systems that will enable the assessment of atherosclerotic plaque sizes or even discovery of novel biomarkers that precede atherosclerotic development will aid in the development of trials. According to Moss et al., researchers might consider recruiting younger subjects and exploring markers of atherosclerosis initiation [275]. However, it is important to note that, this approach would require stratification by risk as flavonoids may have little to no influence on disease in healthy populations.

Another major challenge against the potential use of flavonoids is the lack of a comprehensive understanding of their pharmacokinetic profiles in humans [276]. Overall, most flavonoids appear to have a low bioavailability, that is determined by the nature of the attached sugar and many other factors such as individual differences regarding the microbiota, digestive enzymes, and/or dietary habits [277]. To overcome this problem, researchers have employed multiple methods over the years with other nutraceuticals such curcumin which include the use of adjuvants such as absorption enhancers [278], formulating liposomal products [275] or novel delivery systems [279], shifting the site of absorption from large intestine to small intestine [280]. Future investigations evaluating the pharmacological response of these newer forms against standard compounds are a great step toward therapeutic use of flavonoids for atherosclerosis.

Research has also led to ongoing debate as to whether antioxidant supplementation actually benefits health [281]. There is also some concern that excessive doses of antioxidant supplements may be unsafe. For example, a meta-analysis linked the use of vitamin E supplements to a 22% increased risk of hemorrhagic stroke [282]. Moreover, two important randomized trials, the Women’s Health Study [283] and the Women’s Antioxidant Cardiovascular Study [284], have concluded that in most cases, antioxidant supplements did not help to prevent disease. In addition to this, it is also well-established that a baseline redox imbalance level is fundamental for cellular adaptation [285] and can actually improve endogenous antioxidant defense systems [285,286]. It is a severe redox imbalance that generally results in extensive damage and cell toxicity. For example, exercise produces low ROS levels which are essential for the exercise-induced adaptive response in skeletal muscles [287] and enhancement of classical antioxidant enzymes expression [288]. One of the most important properties of flavonoids is their antioxidant activity [289]. As such, pharmacological antioxidant supplementation may not be as beneficial as previously thought due to the elimination of low-level ROS production [288].

Important evidence now suggests that flavonoids, can under certain conditions, even act as pro-oxidants. This is also a property of many other antioxidants [277]. For flavonoids, pro-oxidant activity appears to be related to structural properties including the total number of hydroxyl groups per molecule [290]. For example, quercetin, especially at higher doses, exhibits oxidant induced noxious effects related to mutagenicity and mitochondrial toxicity [291]. This occurs through oxidation of quercetin by a number of peroxidases, into toxic metabolites [269] that are extremely reactive toward thiols, such as GSH. This phenomenon has been defined as ‘the quercetin paradox’ and leads to significant reductions in GSH levels [292]. This may be particularly important in subjects with increased oxidative stress correlated with clinical conditions such as diabetes mellitus and obesity [277]. It is expected that many of these patients may already have low GSH, making them even more sensitive to harmful oxidation effects.

Flavonoids still lack robust scientific evidence to endorse their clinical use. Future investigations on safety, bioavailability, dosage and adverse effects are crucial in order to introduce flavonoids as pharmacological agents [145,266]. Moreover, long-term randomized controlled trials are crucial to fully assess the clinical benefit of flavonoid supplementation and mechanistic studies are needed to better understand the molecular mechanisms involved in the protective action of these compounds.

Competing Interests

The authors declare that there are no competing interests associated with the manuscript.

Funding

This publication was made possible by an MPP fund [grant number 320133] and a Farouk Jabre Award from the American University of Beirut (to Ali H. Eid).

Acknowledgements

We would like to thank Miss Hana El Osman for her help with the illustrations.

Abbreviations

     
  • ABCAl and ABCG1

    adenosine triphosphate binding cassette sub-families A1 and G1

  •  
  • ABCG8

    adenosine triphosphate binding cassette sub-family G1

  •  
  • ABTS

    (2,2′‐azino‐bis (3‐ethylbenzothiazolinine‐6‐sulfonic acid)

  •  
  • ACAT

    acyl-CoA cholesterol acyltransferase

  •  
  • ACC

    acetyl-CoA carboxylase

  •  
  • ADMA

    asymmetric dimethylarginine

  •  
  • AMPK

    adenosine monophosphate activated protein kinase

  •  
  • ApoB-100

    Apo lipoprotein B-100

  •  
  • ApoE

    Apo lipoprotein E

  •  
  • ATI

    adipose tissue inflammation

  •  
  • C/EBP α

    CCAAT/enhancer binding protein α

  •  
  • CAM

    cell adhesion molecule

  •  
  • CCL19

    chemokine ligand 19

  •  
  • CD80 and CD86

    cluster of differentiation 80 and 86

  •  
  • CDK

    cyclin-dependent kinase

  •  
  • cGM

    cyclic guanosine monophosphate

  •  
  • COX-1

    cyclooxygenase-1

  •  
  • CPT1a

    carnitine palmitoyltransferase 1A

  •  
  • CRP

    C-reactive protein

  •  
  • CVD

    cardiovascular disease

  •  
  • CYP 1A1

    cytochrome P450 1A1

  •  
  • DAG

    diacylglycerol

  •  
  • DDAH II

    dimethylarginine dimethylaminohydrolase

  •  
  • DGAT1 and DGAT2

    diacylglycerol O-acyltransferase 1 and 2

  •  
  • DMPD

    (N,N‐dimethyl‐p‐phenylenediamine dihydrochloride)

  •  
  • EC

    epicatechin

  •  
  • EGCG

    epigallocatechin gallate

  •  
  • eNOS

    endothelial nitric oxide synthase

  •  
  • ER

    estrogen receptors

  •  
  • ERK1/2

    extracellular signal-regulated kinase 1 and 2

  •  
  • Esel

    E-selectin

  •  
  • FAS

    fatty acid synthase enzyme

  •  
  • GSH-Px

    glutathione peroxidase

  •  
  • HDL

    high-density lipoprotein

  •  
  • HFD

    high fat diet

  •  
  • HMG-CoA

    3-hydroxy-3-methylglutaryl-Coenzyme A reductase

  •  
  • HO-1

    heme oxygenase 1

  •  
  • HUVECS

    human umbilical vein endothelial cells

  •  
  • ICAM-1

    intracellular adhesion molecule 1

  •  
  • IFNα

    interferon alpha

  •  
  • IFNγ

    interferon γ

  •  
  • IL-1β

    interleukin 1 beta

  •  
  • IL-1

    interleukin 1

  •  
  • IL-4

    interleukin 4

  •  
  • IL-6

    interleukin 1

  •  
  • IL-12

    interleukin 12

  •  
  • IκB

    inhibitor of kappa B

  •  
  • JNK

    c-jun-N-terminal kinase

  •  
  • LDL

    low-density lipoprotein

  •  
  • LDLR

    low-density lipoprotein receptor

  •  
  • LXR-α

    liver x receptor alpha

  •  
  • MAPK

    mitogen-activated protein kinase

  •  
  • MCP-1

    protein monocyte chemotactic-1

  •  
  • MDA

    malondialdehyde

  •  
  • mTOR

    mammalian target of rapamycin

  •  
  • NF-κB

    nuclear factor kappa-light-chain-enhancer of activated B-cells

  •  
  • NO

    nitric oxide

  •  
  • NOX

    nicotinamide adenine dinucleotide phosphate oxidase

  •  
  • NOX4

    nicotinamide adenine dinucleotide phosphate oxidase 4

  •  
  • Nrf-2

    nuclear factor erythroid 2-related factor 2

  •  
  • O-DMA

    O-desmethylangolensin

  •  
  • ox-LDL

    oxidized LDL

  •  
  • p21

    cyclin-dependent kinase inhibitor protein 21

  •  
  • PAP

    phosphatidate phosphohydrolase

  •  
  • PI3K

    phosphoinositide 3-kinase

  •  
  • PLC- γ2

    phosphatidylinositol-4,5-isphosphate phosphodiesterase gamma-2

  •  
  • PPARα

    peroxisome proliferator-activated receptor alpha

  •  
  • PPARγ

    peroxisome proliferator-activated receptor gamma

  •  
  • PVAT

    perivascular adipose tissue

  •  
  • RCT

    reverse cholesterol transport

  •  
  • ROS

    reactive oxygen species

  •  
  • SAT

    subcutaneous adipose tissue

  •  
  • SOD1/2

    superoxide dismutase 1/2

  •  
  • SR-BI

    scavenger receptor class B type 1

  •  
  • SREBP-1

    sterol regulatory element-binding protein 1

  •  
  • sSMase

    sphingomyelinase

  •  
  • TAG

    Triacylglycerol

  •  
  • TG

    triglyceride

  •  
  • TLR-2

    toll-like receptor 2

  •  
  • TLR-4

    toll-like receptor 4

  •  
  • TNF-α

    tumor necrosis factor alpha

  •  
  • TZD

    thiazolidinediones

  •  
  • VAT

    visceral adipose tissue

  •  
  • VCAM-1

    vascular cell adhesion molecule 1

  •  
  • VLCAD

    very long-chain acyl CoA dehydrogenase

  •  
  • VLDL

    very low-density lipoprotein

  •  
  • VSMC

    vascular smooth muscle cell

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