The CXC chemokines, CXCL4, -9, -10, -11, CXCL4L1, and the CC chemokine CCL21, activate CXC chemokine receptor 3 (CXCR3), a cell-surface G protein-coupled receptor expressed mainly by Th1 cells, cytotoxic T (Tc) cells and NK cells that have a key role in immunity and inflammation. However, CXCR3 is also expressed by vascular smooth muscle and endothelial cells, and appears to be important in controlling physiological vascular function. In the last decade, evidence from pre-clinical and clinical studies has revealed the participation of CXCR3 and its ligands in multiple cardiovascular diseases (CVDs) of different aetiologies including atherosclerosis, hypertension, cardiac hypertrophy and heart failure, as well as in heart transplant rejection and transplant coronary artery disease (CAD). CXCR3 ligands have also proven to be valid biomarkers for the development of heart failure and left ventricular dysfunction, suggesting an underlining pathophysiological relation between levels of these chemokines and the development of adverse cardiac remodelling. The observation that several of the above-mentioned chemokines exert biological actions independent of CXCR3 provides both opportunities and challenges for developing effective drug strategies. In this review, we provide evidence to support our contention that CXCR3 and its ligands actively participate in the development and progression of CVDs, and may additionally have utility as diagnostic and prognostic biomarkers.

INTRODUCTION

Death rates from cardiovascular diseases (CVDs) have declined, yet the burden remains high. It has been estimated that 17.5 million people globally died from CVDs in 2012 [1], and it has been computed that this number will increase to more than 24 million by 2030 [2]. This prediction is mainly driven by the fact that population growth and improved longevity are increasing the number and proportion of older people. As a result, CVDs, which are notoriously age-dependent pathologies, are legitimately expected to grow.

Seminal studies demonstrated that prototypical inflammatory cytokines are involved in adverse remodelling of the heart [3]. For instance, elevated levels of circulating tumour necrosis factor-alpha (TNF-α) were described in patients with heart failure by Levine et al. [4], and circulating levels of pro-inflammatory cytokines TNF-α and interleukin (IL)-6 were found to be increased in patients as their functional heart failure classification deteriorated [5]. The salient points of the research performed on inflammation in heart failure that supports the Cytokine Hypothesis of Heart Failure were reviewed by Braunwald [6]. Consistent evidence from both pre-clinical and clinical studies suggests a multifactorial role of cytokines in early myocardial dysfunction and disease progression [7,8]. Levels of pro-inflammatory cytokines in the circulation of patients with heart failure, including TNF-α [9], IL-1β [10], IL-6 [11] and IL-18 [12], have a direct correlation to worsening of the disease. Munger et al. [13] were one of the first to investigate a relation between the increase in circulating IL-6 and the New York Heart Association (NYHA) functional classification of heart failure. Their major finding was that arterial IL-6 is progressively increased from mild to severe heart failure, showing a direct correlation with NYHA score [12]. Also, Yamaoka-Tojo et al. [14] observed that IL-18, a molecule with pleiotropic activity, but known to activate pro-inflammatory cytokines/chemokines, increases in relation to the severity of congestive heart failure [14]. Strong evidence links increased circulating levels of TNF-α and NYHA score [1517], although clinical trials involving etanercept and infliximab were not successful [18]. Similarly, multiple reports on the role of IL-1β in CVDs suggest the possibility that an IL-1β inhibitor may be a potential agent to restrain development of heart failure [19]. Clinical trials with the IL-1 receptor antagonist, anakinra are ongoing to assess its efficacy in various forms of heart failure and acute myocardial infarction (AMI).

Similar to cytokines, elevated circulating chemokine levels have been found to be associated with cardiac dysfunction in both pre-clinical models for CVDs and in patients [20]. Chemokines are a subclass of cytokines. The name chemokine reflects the fact that these cytokines direct chemotaxis in nearby responsive cells. This review focuses on the recent evidence that one particular subclass of chemokines, which activate the CXCR3 receptor, is actively involved in many adverse cardiovascular conditions, as well as serving as predictors for heart failure progression.

CHEMOKINE OVERVIEW

Chemokines are a subclass of cytokines that bind to a family of 20 Class 1 (rhodopsin-like) G protein-coupled receptors (GPCRs). They are characterized by their small size (8–10 kDa) and distinctive 3D structure that is stabilized by intramolecular disulphide bonds. The N-terminus is used to group chemokines into four subfamilies based on the arrangement of the first two of four conserved cysteine (C) residues: CC, CXC, CX3C and C. In the CC subfamily, the first two cysteines are adjacent; in CXC, the cysteines are separated by one amino acid (X); for CX3C, the two cysteine residues are separated by three amino acids and C chemokines lack the first and third conserved cysteine residues.

Chemokines are primarily involved in leucocyte trafficking, but act on other cells as well [21,22]. The C chemokines primarily recruit lymphocytes and the CC chemokines monocytes, lymphocytes, natural killer (NK) cells, dendritic cells, eosinophils and basophils. Fractalkine (CX3CL1), the only known CX3C chemokine, functions as a chemoattractant for T lymphocytes, NK cells, dendritic cells and monocytes and as an adhesion molecule for leucocytes (including monocytes) on activated endothelial cells [23]. CXC chemokines are involved in leucocyte trafficking, as well as vascular smooth muscle cell (VSMC) and endothelial cell proliferation and motility [24]. CXC chemokines can be further subdivided based on the presence of a tripeptide ELR (Glu-Leu-Arg) motif preceding the first conserved cysteine residue [25]. ELR+ CXC chemokines attract neutrophils and have more angiogenic properties, whereas the ELR− CXC chemokines are lymphocyte attractants with angiostatic properties. The CXCR3 ligands, CXCL4, -9, -10 and -11, are ELR− CXC chemokines.

Chemokine membrane receptors are primarily expressed by leucocytes [26], and chemokines were first identified as regulators of the homing and migration of immune cells. However, recent evidence has shown that chemokine receptors are expressed by endothelial cells in the heart; but further investigation is needed to establish the pathophysiological relevance of this observation [27]. A specific chemokine generally binds to and activates one subfamily of receptor in a cell-type specific manner, although one receptor-type may bind multiple chemokines [22]. Different chemokines may activate different signalling pathways and elicit different responses via the same receptor [28]. The basis for this signalling selectivity is not established, but probably reflects the feature of biased signalling that characterizes GPCRs in general [28]. Most, if not all GPCRs signal via two distinct modes: G protein-dependent and β-arrestin-dependent signalling pathways. Thus, it seems likely that different chemokines acting on the same receptor activate one or the other pathway to a varying extent.

One of the best-studied chemokines in cardiac/fibrotic remodelling is monocyte chemoattractant protein-1 (MCP-1), also known as chemokine (C–C motif) ligand 2 (CCL2). In response to an insult to the myocardium (e.g., pressure overload or brief ischaemia), MCP-1 through binding to the receptor CCR2 elicits chemotaxis and activation of β1 integrin-dependent adhesion of monocytic cells [29]. The recruited mononuclear cells trigger activation of inhibitory pathways, mostly directed by the cytokine TGF-β, suppressing the inflammatory state while inducing cardiac fibrosis [30]. Hence, MCP-1 downstream signalling post-myocardial infarction (MI) initially activates a pro-inflammatory response, which triggers in a second stage the resolution of inflammation and scar maturation. In addition, recent evidence indicates that MCP-1 may have direct, protective effects on cardiac myocytes against ischaemia [31,32].

THE CXCR3 CHEMOKINES

An increasing body of evidence shows that the CXC receptor 3 (CXCR3) and its ligands actively participate in the pathophysiological milieu of cardiac diseases (Figure 1). The chemokine receptor CXCR3, like all GPCRs, consists of seven-transmembrane spanning domains and is normally highly expressed on the surface of both resting and activated T lymphocytes. It is also expressed on numerous other immune and non-immune cell types. Interestingly, the Cxcr3 gene is conserved in human, chimpanzee, Rhesus monkey, dog, cow, mouse, rat, zebrafish and frog, which means that pre-clinical in vivo studies have strong translational potential.

Involvement of CXCR3 in CVDs

Figure 1
Involvement of CXCR3 in CVDs

All CXCR3 chemotactic ligands are up-regulated during CVDs and constitute potential prognostic/diagnostic biomarkers. CXCR3 ligands direct involvement through CXCR3 varies depending on the CVD. Atherosclerosis involves CCL21, CXCL9 and CXCL10; both hypertension and myocarditis involve CXCL9, CXCL10 and CXCL11; heart failure, cardiac transplant and myocardial infarction involve CCL21, CXCL9, CXCL10 and CXCL11. CXCR3 ligands may affect CVDs independently of CXCR3 by proteoglycan signalling and possible undefined mechanisms. CVDs can also maintain CXCR3 ligand levels in a self-sustaining loop. See text for details.

Figure 1
Involvement of CXCR3 in CVDs

All CXCR3 chemotactic ligands are up-regulated during CVDs and constitute potential prognostic/diagnostic biomarkers. CXCR3 ligands direct involvement through CXCR3 varies depending on the CVD. Atherosclerosis involves CCL21, CXCL9 and CXCL10; both hypertension and myocarditis involve CXCL9, CXCL10 and CXCL11; heart failure, cardiac transplant and myocardial infarction involve CCL21, CXCL9, CXCL10 and CXCL11. CXCR3 ligands may affect CVDs independently of CXCR3 by proteoglycan signalling and possible undefined mechanisms. CVDs can also maintain CXCR3 ligand levels in a self-sustaining loop. See text for details.

There are three isoforms of CXCR3 in humans: CXCR3-A, CXCR3-B and chemokine receptor 3-alternative (CXCR3-alt) [33]. In rodents, the CXCR3 receptor has a mature form that is similar to human CXCR3-A, and the ligand profile is identical (Table 1). Two additional alternatively spliced variants of the human CXCR3 receptor occur, CXCR3-B and CXCR3-alt [34,35]. CXCR3-B has a longer N-terminus than CXCR3-A, and is mainly expressed on microvascular endothelial cells. The much smaller CXCR3-alt has a similar but much lower expression pattern to CXCR3-A, and is of unknown physiological relevance. What importance these CXCR3 isoforms have in determining the biological function of their ligands in human CVDs is unclear. In addition, CXCL10 and likely the other CXCR3 ligands exert biological actions independent of CXCR3 by binding to proteoglycans. For instance, the anti-fibrotic actions of CXCL10 in the infarcted myocardium occur via cell surface proteoglycan signalling and inhibition of growth factor-mediated fibroblast migration [36]. CXCL10-mediated inhibition of endothelial cell migration also occurs through proteoglycan signalling, although the angiostatic actions of CXCL10 require CXCR3 [37].

Table 1
Fundamental characteristic of the CXCR3 isoforms
Rodents
Mus MusculusRattus NorvegicusHomo sapiens
Gene symbol (HGNC) Cxcr3 Cxcr3 CXCR3 
Gene accession (length) NC_000086
(2.612 bp) 
NC_005120
(2.652 bp) 
 NG_029076.1
(9.602bp) 
 
Genomic position X D Xq31 Xq13 
CXCR3+ cells source Spleen, thymus and lung Spleen, thymus, lung, uterus, kidney, heart, adrenal gland, liver and testis Higher expression levels seen in lymph node, leucocytes, spleen and appendix 
KEGG signalling pathways Cytokine–cytokine receptor interaction and chemokine signalling pathway Cytokine–cytokine receptor interaction and chemokine signalling pathway Cytokine–cytokine receptor interaction and chemokine signalling pathway 
Splice isoforms CXCR3 CXCR3 CXCR3A CXCR3B CXCR3-alt 
Transcript (length) NM_009910
(1.609 bp) 
NM_053415
(1.678 bp) 
NM_001504 (1.670 bp) NM_001142797
(1.914 bp) 
NA 
Mature protein (length) NP_034040
(367 aa) 
NP_445867
(367 aa) 
NP_001495
(368 aa) 
NP_001136269
(415 aa) 
(267 aa) 
UniProt ID O88410 Q9JII9 P49682 P49682-2 P49682-3 
Coupled subunit   Gαi or a Gαq   
Subcellular location Cell membrane Cell membrane Cell membrane Cell membrane Cell membrane 
Ligands binding CXCL9, CXCL10,
CXCL11 and CCL21 
CXCL9, CXCL10,
CXCL11 and CCL21 
CXCL9, CXCL10,
CXCL11 and CCL21 
CXCL4, CXCL9, CXCL10 and CXCL11 CXCL11 
Rodents
Mus MusculusRattus NorvegicusHomo sapiens
Gene symbol (HGNC) Cxcr3 Cxcr3 CXCR3 
Gene accession (length) NC_000086
(2.612 bp) 
NC_005120
(2.652 bp) 
 NG_029076.1
(9.602bp) 
 
Genomic position X D Xq31 Xq13 
CXCR3+ cells source Spleen, thymus and lung Spleen, thymus, lung, uterus, kidney, heart, adrenal gland, liver and testis Higher expression levels seen in lymph node, leucocytes, spleen and appendix 
KEGG signalling pathways Cytokine–cytokine receptor interaction and chemokine signalling pathway Cytokine–cytokine receptor interaction and chemokine signalling pathway Cytokine–cytokine receptor interaction and chemokine signalling pathway 
Splice isoforms CXCR3 CXCR3 CXCR3A CXCR3B CXCR3-alt 
Transcript (length) NM_009910
(1.609 bp) 
NM_053415
(1.678 bp) 
NM_001504 (1.670 bp) NM_001142797
(1.914 bp) 
NA 
Mature protein (length) NP_034040
(367 aa) 
NP_445867
(367 aa) 
NP_001495
(368 aa) 
NP_001136269
(415 aa) 
(267 aa) 
UniProt ID O88410 Q9JII9 P49682 P49682-2 P49682-3 
Coupled subunit   Gαi or a Gαq   
Subcellular location Cell membrane Cell membrane Cell membrane Cell membrane Cell membrane 
Ligands binding CXCL9, CXCL10,
CXCL11 and CCL21 
CXCL9, CXCL10,
CXCL11 and CCL21 
CXCL9, CXCL10,
CXCL11 and CCL21 
CXCL4, CXCL9, CXCL10 and CXCL11 CXCL11 

CXCR3 undergoes agonist-induced endocytosis, which at least for T lymphocytes (both resting and activated) is partly mediated by arrestins and, in striking contrast with most other GPCRs, occurs independently of clathrin and caveolae [38]. Normally, internalized chemokine receptors are recycled and reappear on the cell surface within an hour, whereas internalized CXCR3 was found to be largely degraded [38]. Both lysosomes and the proteosome appear to contribute to degradation. Belated replenishment of CXCR3 on the cell surface was dependent on gene expression and de novo protein maturation, a process taking up to several hours. CXCR3 responsiveness is dampened as well by constitutive internalization and is affected by posttranslational modifications that affect ligand binding, such as tyrosine sulfation and N-linked glycosylation [39]. It has been suggested that tight regulatory control of CXCR3 cell surface expression and responsiveness is necessary to preclude excessive amplification of T-lymphocyte recruitment by an autocrine loop, as Th1-polarized lymphocytes are a rich source of interferon-gamma (IFN-γ) that in turn up-regulates the chemotactic CXCR3 ligands. The ligands CXCL9, -10, -11 are also commonly called interferon (IFN)-γ-inducible chemokines (Table 1) [40].

To date, there are six known CXCR3 chemokine ligands:

  • CXCL4 (aka platelet factor-4, PF-4)

  • CXCL4L1 (aka PF-4var)

  • CXCL9 (aka monokine induced by gamma-interferon, MIG)

  • CXCL10 (aka interferon-induced protein of 10 kDa, IP-10)

  • CXCL11 (aka interferon-inducible T-cell alpha chemoattractant, I-TAC)

  • CCL21 (aka beta chemokine exodus-2)

CXCL4 is released from the α-granules of activated platelets and is only weekly chemotactic for neutrophils, monocytes and fibroblasts–if at all [41]. CXCL4 is an inhibitor of endothelial cell proliferation and migration either via interaction with CXCR3-B or by other means [4244]. By binding to heparin-like molecules on the endothelial surface of blood vessels, CXCL4 promotes blood coagulation, which may contribute to wound repair [43,45]. Then again, CXCL4 promotes thrombosis and may play a role in acute coronary syndrome (ACS) [43]. CXCL4 is involved in monocyte arrest on endothelial cells and induction of atherosclerotic lesions as well [46]. CXCL4 also stimulates monocytes to induce endothelial cell apoptosis, which may contribute to plaque progression and disruption [47]. CXCL4L1, the non-allelic variant of CXCL4, is the more potent angiostatic chemokine [48], as well as a chemoattractant like CXCL4 for activated T cells, NK cells and immature dendritic cells [49]. Unlike CXCL4, CXCL4L1 induces chemokinesis of endothelial cells, but in contrast with CXCL4 does not affect endothelial cell proliferation and monocyte recruitment [50]. CXC4L1 seems to be constructively released by platelets and smooth muscle cells and is inducible in monocytes by inflammatory mediators [51,52]. Plasma levels of CXCL4 and CXCL4L1were reported to be elevated in patients with ACS [53]. Surprisingly, low blood levels of CXCL4L1 were recently associated with poor outcome in patients with stable coronary artery disease (CAD) and preserved left ventricular function, independent of NT-proBNP levels [44]. CXCL9, CXCL10 and CXCL11 are three closely related chemokines that are induced by IFN-γ and differentially regulated by other stimuli [54]. They act as potent chemoattractants for monocytes, T cells, NK cells and dendritic cells. Differences among the three are described elsewhere [54]. CCL21 belongs to the CC chemokine family properly and interacts with CCR7 [54]. CCL21 has also been shown to interact with CXCR3, albeit under limited scenarios to date [5557]. The contribution of the CCL21–CXCR3 axis to CVDs is not defined.

CXCR3 AND LIGANDS IN CVDs: A CLOSER LOOK

The pleiotropic nature of the CXCR3 ligands has been studied in cancer, infections, autoimmune diseases and heart transplantation. The last two conditions provided the first evidence that CXCR3 and its ligands function in the heart [5861]. Increasing evidence from pre-clinical (Table 2) and clinical (Table 3) studies indicates CXCR3 ligands are actively involved in CVDs. The challenge is to exploit their clinical potential as diagnostic and prognostic biomarkers, and therapeutic targets.

Table 2
Cardiac implications of CXCR3 and ligands in pre-clinical investigations on adverse cardiac remodelling and CVDs related risk factors

Abbreviations: bFGF, basic fibroblast growth factor; CCC, chronic Chagas cardiomyopathy; HO-1, haem oxygenase-1; I/R, ischaemia / reperfusion; IPC, ischaemic preconditioning; LV, left ventricle; MAP, mean arterial pressure; MRP-14, myeloid-related protein-14; WT, wild type.

Experimental outcome
Pathological mechanismModelCXCR3CCL21CXCL9CXCL10CXCL11
Atherosclerosis Swine  • Expressed in EAT of swine with CAD [73   
Cardiac response to impairment Beagle dogs, mongrel dogs, C57BL/6, BALB/c, Fisher 344 rats • CXCR3+ cells of the type 1 immune response are associated with the development of cardiac pathology in CCC [135]
• CD8+ T cells invading the heart cause lethal myocardial injury [58
 • Up-regulated in the heart following viral and non-viral myocarditis and remains elevated during chronic infection [126128]
• Secreted by murine cardiac endothelial cells following IFN-γ and B. burgdorferi stimulation [142
• Depletion in mice with myocarditis results in increased survival rate and improved heart morphology [130]
• Up-regulated in the heart following viral and non-viral myocarditis [126129]
• Increased transcription in young rats subjected to IPC [143]
• Canine heart is a significant source of CXCL10 following endotoxaemia [144
• Mouse heart is a significant source of CXCL11 following endotoxaemia [145
Cardiac hypertrophy C57BL/6  • Increased mRNA and protein levels in myocardium following LV pressure overload [86• Elevated circulating levels in TAC mice [88,89• Promoter acetylated and gene activated in TAC mice [87]
• Elevated circulating levels in TAC mice [88,89
 
Heart transplant BALB/c, C57BL/6, CXCR3−/−,
A/J (H-2(a))
MRP-14−/−, Sprague–Dawley (SD) rats 
• Expression in myocardium is associated with decrease allograft heart survival [133]
• Expressed by PBMC [146]
• Expressed on CXCR3 memory T cells [134]
• Decrease HO-1 gene induction [147
• Elevated in lymphatic vessels following rat cardiac allograft [93• Gene expression and serum concentration are markedly higher during acute allograft rejection [95,96]
• Promotes the development of IFN-γ-producing CD8+ T cells [97
• Antagonizes the development of IFN-γ-producing CD8+ T cells [97]
• Significantly up-regulated in cardiac tissue during rejection [96,98
• Increased gene expression in allograft [96,99]
• Recruits CD4+ T cells in both acute and chronic rejection in rats [100
Hypertension Goldblatt hypertensive rats,
CXCR3−/− mice 
• CXCR3−/− mice have higher MAP and are much more salt sensitive compared with WT [148 • Increased expression with ischaemic nephropathy caused by antihypertensive therapy in the Goldblatt rats [109• Increased expression with ischaemic nephropathy caused by antihypertensive therapy in the Goldblatt rats [109 
Myocardial Infarction In vitro, C57BL/6, CXCR3−/− mice,
I/R mongrel dogs 
• CXCR3+ cells moderate neutrophil recruitment and accelerate myofibroblast infiltration in the infarcted heart [36  • Up-regulated in the infarcted myocardium [36,149]
• Inhibits bFGF-induced cardiac fibroblast migration [36]
• IP-10 mRNA expression remains high within the first hours following reperfusion and permanent MI [92,123
 
Experimental outcome
Pathological mechanismModelCXCR3CCL21CXCL9CXCL10CXCL11
Atherosclerosis Swine  • Expressed in EAT of swine with CAD [73   
Cardiac response to impairment Beagle dogs, mongrel dogs, C57BL/6, BALB/c, Fisher 344 rats • CXCR3+ cells of the type 1 immune response are associated with the development of cardiac pathology in CCC [135]
• CD8+ T cells invading the heart cause lethal myocardial injury [58
 • Up-regulated in the heart following viral and non-viral myocarditis and remains elevated during chronic infection [126128]
• Secreted by murine cardiac endothelial cells following IFN-γ and B. burgdorferi stimulation [142
• Depletion in mice with myocarditis results in increased survival rate and improved heart morphology [130]
• Up-regulated in the heart following viral and non-viral myocarditis [126129]
• Increased transcription in young rats subjected to IPC [143]
• Canine heart is a significant source of CXCL10 following endotoxaemia [144
• Mouse heart is a significant source of CXCL11 following endotoxaemia [145
Cardiac hypertrophy C57BL/6  • Increased mRNA and protein levels in myocardium following LV pressure overload [86• Elevated circulating levels in TAC mice [88,89• Promoter acetylated and gene activated in TAC mice [87]
• Elevated circulating levels in TAC mice [88,89
 
Heart transplant BALB/c, C57BL/6, CXCR3−/−,
A/J (H-2(a))
MRP-14−/−, Sprague–Dawley (SD) rats 
• Expression in myocardium is associated with decrease allograft heart survival [133]
• Expressed by PBMC [146]
• Expressed on CXCR3 memory T cells [134]
• Decrease HO-1 gene induction [147
• Elevated in lymphatic vessels following rat cardiac allograft [93• Gene expression and serum concentration are markedly higher during acute allograft rejection [95,96]
• Promotes the development of IFN-γ-producing CD8+ T cells [97
• Antagonizes the development of IFN-γ-producing CD8+ T cells [97]
• Significantly up-regulated in cardiac tissue during rejection [96,98
• Increased gene expression in allograft [96,99]
• Recruits CD4+ T cells in both acute and chronic rejection in rats [100
Hypertension Goldblatt hypertensive rats,
CXCR3−/− mice 
• CXCR3−/− mice have higher MAP and are much more salt sensitive compared with WT [148 • Increased expression with ischaemic nephropathy caused by antihypertensive therapy in the Goldblatt rats [109• Increased expression with ischaemic nephropathy caused by antihypertensive therapy in the Goldblatt rats [109 
Myocardial Infarction In vitro, C57BL/6, CXCR3−/− mice,
I/R mongrel dogs 
• CXCR3+ cells moderate neutrophil recruitment and accelerate myofibroblast infiltration in the infarcted heart [36  • Up-regulated in the infarcted myocardium [36,149]
• Inhibits bFGF-induced cardiac fibroblast migration [36]
• IP-10 mRNA expression remains high within the first hours following reperfusion and permanent MI [92,123
 
Table 3
Cardiac implications of CXCR3 and ligands in clinical related CVDs

Abbreviations: AS, aortic stenosis; CHD, coronary heart disease; CCC, chronic Chagas cardiomyopathy; IPAH, idiopathic pulmonary arterial hypertension; I/R, ischaemia/reperfusion; PAH, pulmonary arterial hypertension; RHD, rheumatoid heart disease; TCAD, transplant coronary artery disease.

Clinical outcome
Clinical settingCXCR3CCL21CXCL9CXCL10CXCL11
Atherosclerosis   • Expressed in coronary plaques of AMI patients [82• Elevated expression in PBMC from patients with ACS [81]
• Associated with ischaemic stroke [150]
• Elevated in serum of patients with stable CHD [83]
• Expressed in coronary plaques [151
 
Cardiac response to impairment • CXCR3 expression positively correlates to cardiac clinical forms of Chagas disease [136 • Expressed in Chagas cardiomyopathy [132• Expressed in Chagas cardiomyopathy [132 
Heart disease   • Highly expressed in in the valvular tissue of RHD patients [152]
• Regulates local expression of chemokines regulating myocardial inflammatory cell migration in CCC patients [132
• Regulates local expression of chemokines regulating myocardial inflammatory cell migration in CCC patients [132 
Heart failure • CD3+ CXCR3+ cells significantly increased in HF patients with CAD [139• Plasma levels are associated with all-cause and CV mortality in patients with chronic HF [153• Elevated circulating levels in patients with LV dysfunction and associated with the progression to HF [89• Increased in plasma of patients with right ventricular dysfunction with IPAH [154]
• Elevated circulating levels in patients with LV dysfunction and associated with the progression to HF [89
• Elevated circulating levels in patients with LV dysfunction and associated with the progression to HF [89
Heart transplant • CD3+ positive T cells expressing CXCR3 infiltrate the endocardium of the transplanted heart [101 • Significantly up-regulated in cardiac tissue during rejection [102,103• Required for initiation and development of graft failure and is significantly more elevated in serum of rejectors than in nonrejectors [104]
• Expressed in acute rejection [101
• Elevated serum levels in TCAD patients [105
Hypertension   • Elevated circulating levels in treatment-naïve patients [110• Circulating levels are highly increased in patients with systo-diastolic hypertension [111,112]
• Elevated circulating levels in treatment-naïve patients [110
• Elevated circulating levels in treatment-naïve patients [110
Myocardial infarction • Significantly expressed in Th1 cells within 24 h in AMI [137• Elevated serum levels are independently associated with mortality in chronic and acute post-MI HF patients [117• Expressed in coronary thrombi aspirated from patients with AMI [82,151]
• Increased in patients with chronic IHD, but lower in the presence and extent of coronary collaterals [121
• Elevated within the first 24 h in serum of STEMI patients [155]
• Elevated at day 0 and day 28 in serum of AMI patients [156]
• Increased in patients with chronic IHD, but lower in the presence and extent of coronary collaterals [121
• Increased in patients with chronic IHD, but lower in the presence and extent of coronary collaterals [121
Clinical outcome
Clinical settingCXCR3CCL21CXCL9CXCL10CXCL11
Atherosclerosis   • Expressed in coronary plaques of AMI patients [82• Elevated expression in PBMC from patients with ACS [81]
• Associated with ischaemic stroke [150]
• Elevated in serum of patients with stable CHD [83]
• Expressed in coronary plaques [151
 
Cardiac response to impairment • CXCR3 expression positively correlates to cardiac clinical forms of Chagas disease [136 • Expressed in Chagas cardiomyopathy [132• Expressed in Chagas cardiomyopathy [132 
Heart disease   • Highly expressed in in the valvular tissue of RHD patients [152]
• Regulates local expression of chemokines regulating myocardial inflammatory cell migration in CCC patients [132
• Regulates local expression of chemokines regulating myocardial inflammatory cell migration in CCC patients [132 
Heart failure • CD3+ CXCR3+ cells significantly increased in HF patients with CAD [139• Plasma levels are associated with all-cause and CV mortality in patients with chronic HF [153• Elevated circulating levels in patients with LV dysfunction and associated with the progression to HF [89• Increased in plasma of patients with right ventricular dysfunction with IPAH [154]
• Elevated circulating levels in patients with LV dysfunction and associated with the progression to HF [89
• Elevated circulating levels in patients with LV dysfunction and associated with the progression to HF [89
Heart transplant • CD3+ positive T cells expressing CXCR3 infiltrate the endocardium of the transplanted heart [101 • Significantly up-regulated in cardiac tissue during rejection [102,103• Required for initiation and development of graft failure and is significantly more elevated in serum of rejectors than in nonrejectors [104]
• Expressed in acute rejection [101
• Elevated serum levels in TCAD patients [105
Hypertension   • Elevated circulating levels in treatment-naïve patients [110• Circulating levels are highly increased in patients with systo-diastolic hypertension [111,112]
• Elevated circulating levels in treatment-naïve patients [110
• Elevated circulating levels in treatment-naïve patients [110
Myocardial infarction • Significantly expressed in Th1 cells within 24 h in AMI [137• Elevated serum levels are independently associated with mortality in chronic and acute post-MI HF patients [117• Expressed in coronary thrombi aspirated from patients with AMI [82,151]
• Increased in patients with chronic IHD, but lower in the presence and extent of coronary collaterals [121
• Elevated within the first 24 h in serum of STEMI patients [155]
• Elevated at day 0 and day 28 in serum of AMI patients [156]
• Increased in patients with chronic IHD, but lower in the presence and extent of coronary collaterals [121
• Increased in patients with chronic IHD, but lower in the presence and extent of coronary collaterals [121

Atherosclerosis

Chemokines are pivotal for initiation and progression through all stages of atherosclerosis [62], a major risk factor for adverse cardiac events [63,64]. Atherosclerosis is a chronic inflammatory condition of the arterial wall in which CXCR3 expressing Th1, NK and Tc cells play a critical role in atheromatous plaque progression and eventual disruption. Details on which innate immune cell subsets are involved at the various stages in the progression of atherosclerosis can be found elsewhere [65,66]. The precise contribution of Th1, NK and Tc cells, and their interaction with endothelial cells, VSMC, dendritic cells and macrophages in atherosclerotic disease is an ongoing area of investigation; however, the basics of the following scenario of amplifying circuits are well established [65,66]. Initiating factors in atherosclerosis are endothelial dysfunction, increased vascular permeability, increased plasma levels of low density lipoprotein (LDL) and the increased expression of adhesion molecules on endothelial cells. LDL accumulates in the intima and undergoes oxidation by macrophages and endothelial cells, as well as by VSMC that migrate into the tunica intima from the tunica media and proliferate. Circulating leucocytes are recruited into the intima by pro-inflammatory cytokines and chemokines, such as MCP-1/CCL2, fractalkine and CXCR3 ligands, that are secreted by the endothelial cells in response to the oxidized LDL and plasma LDL. These monocytes differentiate into either dendritic cells or macrophages that may accumulate oxidized LDL to become foam cells. Dendritic cells activate NK cells to secrete IFN-γ and NK cells in turn cause further maturation of dendritic cells. T cells are also recruited into the intima, and dendritic cells are important for the induction of the Th1 phenotype. Both NK cells and Th1 cells produce IFN-γ that contributes to Th1 polarization, activates pro-inflammatory macrophages, and induces apoptosis in VSMC. NK cells may directly assist in T-cell polarization as well. IFN-γ also induces the release of TNF-α by macrophages and dendritic cells that enhances expression of adhesion molecules on endothelial cells. The Th1 subset of CD4+ T cells are the most abundant T-cell population in human atherosclerotic plaques and CXCR3 is required for the generation of Th1 cells. The accumulating lipids, macrophages, fibrous connective tissue, calcium and cellular debris that arises from dead VSMC and the cytolytic actions of oxidized LDL, IFN-γ, NK cells and Tc on macrophages and foam cells constitutes the atheromatous plaque that builds up in the artery wall with the progression of atherosclerosis. The plaque is stabilized by a fibrous coat of extracellular matrix proteins produced by VSMC, but with plaque progression, MI pro-inflammatory macrophages predominate and along with dendritic cells secrete metalloproteinases in response to IFN-γ that degrade the fibrous cap and enhance vulnerability of the plaque to rupture. NK cells may contribute to plaque instability and rupture as well. Tc cells contribute to necrotic core formation and plaque vulnerability by granzyme B- and perforin-mediated killing of VSMC, macrophages and endothelial cells. Unstable plaques are characterized by decreased levels of anti-inflammatory regulatory T (Treg) cells and increased levels of Th1, NK and Tc cells [67]. Ruptured or ulcerated plaques cause formation of a thrombus that precipitates an ACS, such as unstable angina, non-ST elevation MI (NSTEMI) or ST elevation MI (STEMI). As discussed, the platelet-derived CXCR3 chemokines CXCL4 and CXCL4L1 participate in thrombus formation and are reported to be elevated in patients with ACS [53].

Pre-clinical and clinical investigations have established that epicardial adipose tissue (EAT) strongly correlates to the inception and progression of atherosclerosis [68,69]. EAT is a potential source of chemokines and is also known to be associated with incidence of cardiovascular events [7072]. In Ossabaw miniature swine fed with an atherogenic diet to induce atherosclerosis, the CCL21 chemokine was found to be up-regulated in EAT [73]. In the same study, it was observed that excision of coronary EAT decreases progression of coronary atherosclerosis.

CXCL10 is expressed by VSMCs, endothelial cells and macrophages in atherosclerotic plaques at all stages of disease progression, as is CXCR3 [74,75]. The type 1 T helper (Th1) subset of CD4+ T cells play an essential role in the development of atherosclerosis [37] and Th1 cells in atheroma express high levels of CXCR3, which is required for their optimal formation [74,76]. In the LDL deficient receptor mouse model of atherosclerosis, a CXCR3 antagonist was recently shown to significantly inhibit atherosclerotic lesion formation [77]. In addition, genetic deletion of CXCR3 in Apoe−/− mice reduced development of atherosclerotic lesions, which correlated with a decrease in T-cell content of the lesions. Likewise genetic knockout of CXCL10 in Apoe−/− mice significantly decreased lesion area [78]. Peripheral blood mononuclear cells (PBMC) modulate plaque development by expressing critical factors, such as inflammatory mediators and miR-146a, which in turn modulate Th1 function [79,80]. Recent studies report that patients with ACS have PBMCs with elevated expression levels of CXCL10 [81]. Also, expression of CXCL9 has been detected in coronary plaques and is elevated in patients with AMI [82]. Finally, circulating levels of CXCL10 have been found to be elevated in patients with stable coronary heart disease [83].

Cardiac hypertrophy and heart failure

Cardiac hypertrophy is a pathological maladaptive response of the heart to the increased blood pressure of hypertension or to volume overload, as occurs with a myocardial infarction [84,85]. The associated structural and genetic changes compromise heart function and in the long term lead to heart failure, the situation where the heart is unable to adequately pump to maintain blood flow to sustain the body's needs [64]. In models of pressure overload, it has been observed that expression and relative protein abundance of CCL21 are elevated in the myocardium [86]. In a recent study, increased histone acetylation was detected at the CXCL10 promoter in the heart with pressure overload and the gene is activated [87]. In the same animal model, circulating levels of CXCL10 and CXCL9 were found to be up-regulated during cardiac hypertrophy [88].

Currently, there are no reported studies showing an association between CXCR3 and its ligands with cardiac hypertrophy in humans. However, CXCL10 was reported to be elevated in plasma of patients with right ventricular dysfunction and idiopathic pulmonary hypertension. Serum levels of CXCL9, CXCL10 and CXCL11 were elevated in patients with mild to severe left ventricular dysfunction [89,90]. Using these chemokines as biomarkers in combination with the N-terminal of the pro-hormone brain natriuretic peptide (NT-proBNP or BNPT) was proven to improve the risk classification of heart failure patients.

Heart transplant

Patients with end-stage heart failure or severe CAD are most likely to receive a heart transplant from a recently deceased organ donor. Nevertheless, the allograft may entail complications like infection, sepsis and even organ rejection. This last complication may occur in two periods: (1) acute rejection, which is the majority of cases, generally occurs within the first week, and (2) chronic rejection, which might occur at any moment during the rest of the patient's life. Of note, recent scientific evidence has shown that heart transplantation causes ischaemic injury resulting in the activation of myocardial ischaemia-associated genes in both syngeneic and allogeneic grafts [91]. Although not explicitly assessed in the present study, CXCR3 ligands are known to be up-regulated with ischaemia in the myocardium [92].

In a rat model for functional analysis of heart transplant, CXCL9 was found to be expressed at high levels in the lymph nodes, together with CCL21 [93], and in the spleen [94]. CXCL9 is elevated during acute rejection of the heart indicating its critical role for the infiltration of CD4+ T cells in the graft [95,96]. Of note, CXCL9 enhances development of IFN-γ-producing CD8+ T cells, which is antagonized by CXCL10 [97], also up-regulated in cardiac tissue during rejection [98]. CXCL11 expression also increases in the allograft and contributes to CD4+ T cells recruitment in both acute and chronic rejection [99,100].

CXCL9 and CXCL10 are significantly up-regulated in human cardiac tissue during rejection [101103]. CXCL10 was found to be elevated in serum of rejecters and appeared to be required for initiation and development of graft failure [104]. Also, CXCL11 was found to be elevated in serum of patients with severe transplant CAD, which accounts for the vast majority of late graft loss, although the role of CXCL11 in this disease is not yet fully understood [105].

Hypertension

Hypertension is one of the major leading causes for the development of CVDs. The stress induced by high blood pressure and possible enhanced sympathetic outflow is associated with vascular dysfunction, renal impairment and direct actions on the heart that may ultimately cause heart failure. An increasing body of evidence shows that inflammation plays a critical role in the development of hypertension [106]. Chemokines especially have the task to coordinate the recruitment of immune cells to the blood vessels responsible for controlling blood pressure [107,108].

In vivo models for hypertension, such as the Goldblatt hypertensive rat, show increased expression of CXCL9 and CXCL10 in the kidney, which was associated with kidney injury and the up-regulation of fibrogenic proteins and matrix metalloproteinases [109]. Patients with hypertension were reported to have elevated circulating levels of CXCL9, - 10, - 11 [110]. Although there is no study evaluating their variation in response to a medical treatment, it was confirmed that these three circulating CXCR3 ligands are increased in patients with essential hypertension [111,112].

Myocardial infarction

Myocardial infarction is the obstruction of blood flow to one or more areas of the heart, resulting in myocyte death, followed by structural and functional changes in the myocardium, as reflected by chamber remodelling, wall thinning and myocyte slippage, increased fibrosis, dilation and impaired function [113]. Several CXCR3 chemokines are up-regulated in different MI models and play a crucial role in leucocyte trafficking and post-infarct wound healing of the heart [75]. Details as to the temporal phases of the inflammatory-immune response to ischaemic injury can be found elsewhere [114,115]. Briefly, neutrophil granulocytes initially invade the infarcted myocardium to clear debris. These cells are soon followed by NK cells and inflammatory monocytes that can transdifferentiate into dendritic cells or M1 macrophages. Within a week, the pro-inflammatory invading monocytes give rise to reparative M2 macrophages that replace the M1 macrophages. Post-MI, the predominant subsets of CD4+ T cells are Th1 and regulatory T cells [116]. These are accompanied by CD8+ T cells (Tc). The up-regulation of different chemokines at different time points during and post-MI has not been fully defined [75], although evidence indicates a central importance for several CXCR3 chemokines, which are chemoattractants for Th1, Tc and NK cells. Increased serum concentrations of chemokine CCL21 were reported to be independently associated with mortality in chronic and acute post-MI heart failure patients [117]. CXCL10 has been reported to be elevated in serum of ST-elevated myocardial infarcted patients within the first 24 h. In another study, serum CXCL10 was elevated at day 0 and also at day 28 in patients with AMI. CXCL9 is expressed in coronary thrombosis and serum levels are elevated in patients with AMI. The non-ELR CXC chemokine ligands, CXCL4, CXCL9, CXCL10 and CXCL11, are considered strong inhibitors of angiogenesis, which may be beneficial at early stages post-MI as this would reduce ineffective neovascularization before removal of cellular debris and dead cells. On the other hand, patients with chronic ischaemic heart disease (IHD) are likely to develop coronary collaterals, which has a protective effect on the myocardium and is associated with better outcomes in a broad spectrum of patients with varying degrees of IHD burden [118120]. Consistently, CXCL9, CXCL10 and CXCL11 were found to be elevated in patients with chronic IHD and were lower in the presence and with the extent of coronary collaterals [121].

During embryogenesis, the epicardium serves as a source of paracrine factors and cardiovascular precursor cells that are critical in heart formation. CCL5 and CXCL10 are produced by epicardial cells and act as negative regulators of heart morphogenesis. In their recent study, Velecela et al. [122] reported that CCL5 and CXCL10 expression in epicardial cells is repressed by WT1 signalling, a pathway that is involved in the regulation of heart morphogenesis. WT1 was found to inhibit CCL5 and CXCL10 expression both directly and by increasing interferon regulatory factor 7 (IRF7) levels. Functional assays demonstrated that CXCL10 and CCL5 inhibit the migration of epicardial cells and proliferation of cardiomyocytes. These findings have significance for repairing the adult heart as epicardial cell reactivation after myocardial damage is linked with WT1 expression [64]. The reactivated adult epicardium is a source of multipotent cardiovascular progenitor cells and various paracrine factors with diverse roles, including modulation of inflammation and the repair process. Intriguingly, CXCL10 levels in the left ventricle were reported to be elevated in the acute phase following MI in the mouse [123,124].

Evidence from knockout mice indicates that CXCL10 is important acutely post-MI in repairing the heart [125]. Loss of CXCL10 was associated with enhanced adverse remodelling and early expansion of the scar. Knockout mice developed wall thinning and enhanced systolic dysfunction. CXCR3+ cell recruitment was markedly reduced, although expression of inflammatory cytokines and chemokines was little affected. Increased scar formation was attributable in part to enhanced myofibroblast accumulation and collagen deposition, and CXCL10 was observed to attenuate growth factor-induced fibroblast migration. Ventricular wall thinning was attributed to altered mechanical properties of the scar as CXCL10 was found to enhance growth factor-induced contraction of fibroblast-populated collagen lattices. These findings demonstrate the important reparative role of CXCL10 in orchestrating a proper wound healing response in the acute setting of MI.

Myocarditis

Exposure of the heart to certain viruses and microorganisms can lead to cardiac remodelling driven in part by inflammation. Viral myocarditis and Chagas disease are two common inflammatory conditions of the heart due to non-self agents. Although the aetiology differs from the sterile inflammatory response of an MI, there is a common underlying pathophysiology driven by adverse cardiac remodelling. CXCL9 and CXCL10 are up-regulated in the heart post viral and non-viral infection and are strong biomarkers for myocarditis in rodent models [126129]. Interestingly, depletion of CXCL10 in mouse models for Coxsackievirus B3 (CVB3)-induced myocarditis was shown to be beneficial in terms of survival rate and heart morphology by blunting the Th1 immune response [130]. Also, emerging evidence associates CVDs to circulating endotoxaemia [131]. In animal models for endotoxaemia, considerable levels of circulating CXCL10 and CXL11 were observed and apparently the main source was the heart.

Patients affected by Chagas cardiomyopathy, a life-threatening inflammatory dilated cardiomyopathy, have elevated levels of CXCL9 and CXCL10 [132]. Based on the relationship of polymorphisms in CXCL9 and CXCL10 with myocardial chemokine expression and intensity of myocarditis in Chagas cardiomyopathy, Nogueira et al. [132] suggest that these two CXCR3 ligands affect the myocardial expression of other key chemokines. CXCL9 and CXCL10 may thereby function as master regulators of myocardial inflammatory cell migration and key regulators of adverse cardiac remodelling in Chagas disease.

CXCR3 POSITIVE CELLS IN CVDs

Pre-clinical and clinical investigations indicate that CXCR3+ cells invade the myocardium in various adverse events such as heart transplant rejection [101,133,134], Chagas disease [135,136] and myocardial infarction [36,137]. This last condition is the most dramatic insult to the heart and is associated with sudden, severe cardiac remodelling [138]. Athanassopoulos et al. [139] assessed the levels of various chemokine receptors in patients with diverse aetiologies of heart failure (Figure 2). Interestingly, most CD8+ T cells expressed CXCR3, compared with CD4+ T cells. This finding suggests that cytotoxic T cells may take over from the acute response involving Th1 lymphocytes. This may also reflect chronic activation from an early stage based on elevated expression of CXCR3 ligands in those asymptomatic and at higher risk of heart failure [89].

CXCR3 expression among T-lymphocytes in heart failure

Figure 2
CXCR3 expression among T-lymphocytes in heart failure

Levels of CXCR3 expression among circulating T-lymphocytes in advanced heart failure patients of different aetiologies belonging to NYHA class III/IV. The percentages of CD3+, CD4+ and CD8+ lymphocytes that express CXCR3 was determined. Abbreviations: hypertrophic cardiomyopathy (HCM), idiopathic dilated cardiomyopathy (IDCM) and valvular disease (VD). Data were extracted from [139]: Athanassopoulos, P., Vaessen, L.M., Balk, A.H., Weimar, W., Sharma, H.S. and Bogers, A.J. (2006) Altered chemokine receptor profile on circulating leucocytes in human heart failure. Cell Biochem. Biophys. 44, 83–101.

Figure 2
CXCR3 expression among T-lymphocytes in heart failure

Levels of CXCR3 expression among circulating T-lymphocytes in advanced heart failure patients of different aetiologies belonging to NYHA class III/IV. The percentages of CD3+, CD4+ and CD8+ lymphocytes that express CXCR3 was determined. Abbreviations: hypertrophic cardiomyopathy (HCM), idiopathic dilated cardiomyopathy (IDCM) and valvular disease (VD). Data were extracted from [139]: Athanassopoulos, P., Vaessen, L.M., Balk, A.H., Weimar, W., Sharma, H.S. and Bogers, A.J. (2006) Altered chemokine receptor profile on circulating leucocytes in human heart failure. Cell Biochem. Biophys. 44, 83–101.

The importance of the CXCR3 receptor in CVDs is not fully understood, but it is recognized that CXCR3 is mostly expressed by Th1 cells involved in inflammation. However, CXCR3 is also expressed by endothelial cells and VSMCs, and appears to be important in controlling physiological vascular function. Mice lacking the CXCR3 receptor show increased angiotensin II type 1 receptor (AT1) expression and hypertension [83]. CXCR3 is also present on stromal cells of the myocardium, suggesting that cells with supportive function for the heart may be modulated by expression of CXCR3 ligands with CVDs. However, while being up-regulated in the infarcted myocardium, the anti-fibrotic effects of CXCL10 due to inhibition of growth factor-mediated fibroblast migration were recently reported to be independent of CXCR3 and mediated through proteoglycan signalling. CXCR3 null mice exhibited increased peak neutrophil recruitment and delayed myofibroblast infiltration in the infarcted heart; however, CXCR3 knockout mice exhibited comparable scar size and post-infarction remodelling with ischaemia-reperfusion injury as wild type animals [88]. Of course, CXCL10 may have effects on cardiac fibroblasts relevant to wound healing post-MI via both CXCR3 and proteoglycans, but the relative contribution of each may be determined by the extent of the myocardial injury and/or levels of CXCL10. Note that definitive evidence that cardiac fibroblasts or myofibroblasts express CXCR3 is wanting.

THERAPEUTIC ASPECTS

A large number of inflammatory mediators have been identified to date and the field is expanding. Nonetheless, the idea that implementing novel anti-inflammatory drugs may curb the progression of heart disease is gaining credibility. The field of drug discovery focused around CXCR3 and its ligands is at an early stage. Evidence from pre-clinical models indicates that inhibiting CXCR3 is beneficial for heart transplant. AMG1237845, a small non-peptide inhibitor of CXCR3, combined with low-dose anti-CD154 monoclonal antibodies, proved to be immunosuppressive during acute graft rejection in C57BL/6 (H-2) mice receiving vascularized cardiac allografts from A/J (H-2) donors [60]. Similarly, a specific monoclonal antibody for mouse CXCR3 was shown to robustly prolong cardiac and islet allograft survival when injected together with low doses of rapamycin [140]. These early studies establish proof of concept: (1) it is possible to reduce recruitment of CXCR3 positive cells, which in turn benefits the transplanted heart, and (2) with CXCR3 inhibition it is possible to reduce the doses of immunosuppressive agents, which are in themselves highly toxic.

The study of Byrne et al. [141] reported the ineffectiveness of a specific CXCL10 monoclonal antibody in different mouse models of inflammation with high levels of CXCL10, including cardiac allograft transplantation. Thus, targeting CXCR3 may have greater impact on the pathophysiological events than targeting the ligands. However, the relative importance of the CXCR3 receptor and its ligands has not been fully elucidated. For instance, CXCR3 is present on stromal cells of the myocardium and CXCR3 positive cells apparently play a functional role in the injured or diseased heart of various aetiologies, but the beneficial anti-fibrotic actions of CXCL10 in the heart are CXCR3-independent. This latter finding suggests that drug therapies based on CXCR3-inoperative forms of CXCL10 could be a useful anti-fibrotic strategy for the heart.

CONCLUSIONS AND FUTURE PERSPECTIVES

There is strong evidence that CXCR3 and its ligands play a key role in multiple CVDs such as atherosclerosis, hypertension, cardiac hypertrophy and heart failure, as well as in heart transplant rejection and transplant CAD. Unabated inflammation and immune response leading to tissue injury and adverse remodelling are most likely the common denominator. This would explain the fact that circulating levels of ligands such as CXCL9, -10 and -11 increase with the progression of left ventricular dysfunction, or CCL21 with the progression of heart failure. Although not yet fully established, CXCR3 and its ligands would seem to have both beneficial and deleterious actions depending upon timing and their level of activation. For instance, clinical data suggest that CXCR3 ligands by hindering development of coronary collaterals have a negative impact on survival rate in individuals with chronic IHD, yet inhibition of vascularization early post-myocardial infarction is likely important for an effective wound healing process. Similarly, although involved in sustaining inflammation through Th1 recruitment, CXCL10 may also have a role in preventing excessive fibrosis in the infarcted heart. Exploiting the pharmacological potential of targeting CXCR3 ligands in CVDs requires a better understanding of their divergent actions, as well as better resolution of which actions are CXCR3-dependent or -independent. Targeted therapeutic interventions perturbing the CXCR3-axis may provide novel mechanistic insights into its pathophysiology in disease context. In addition, the combination of therapeutic intervention with measurement of circulating CXCR3 positive cells and ligands may provide evidence supporting the validity of CXCR3 ligands as biomarkers of CVD progression.

Dr Altara is extremely grateful for the many stimulating discussions with Dr Struijker-Boudier and Dr Blankesteijn (CARIM, University of Maastricht). Dr Zouein acknowledges the generous support of the Department of Pharmacology and Toxicology, American University of Beirut Faculty of Medicine.

FUNDING

This work was supported by the American University of Beirut [grant number 100410 (to F.A.Z.)].

Abbreviations

     
  • ACS

    acute coronary syndrome

  •  
  • AMI

    acute myocardial infarction

  •  
  • AT1

    angiotensin II type 1 receptor

  •  
  • CAD

    coronary artery disease

  •  
  • CD4+

    cluster of differentiation 4

  •  
  • CVB3

    Coxsackievirus B3

  •  
  • CVD

    cardiovascular disease

  •  
  • CXCL

    CXC chemokine ligand

  •  
  • CXCR

    CXC chemokine receptor

  •  
  • CXCR3-alt

    chemokine receptor 3-alternative

  •  
  • EAT

    epicardial adipose tissue

  •  
  • ELR

    Glu-Leu-Arg motif

  •  
  • GPCR

    G protein-coupled receptor

  •  
  • IFN-γ

    interferon-gamma

  •  
  • IHD

    ischaemic heart disease

  •  
  • IL

    interleukin

  •  
  • LDL

    low density lipoprotein

  •  
  • MCP-1/CCL2

    monocyte chemoattractant protein-1

  •  
  • MI

    myocardial infarction

  •  
  • NT-proBNP

    BNPT, N-terminal of the pro-hormone brain natriuretic peptide

  •  
  • NYHA

    New York Heart Association

  •  
  • PBMC

    peripheral blood mononuclear cells

  •  
  • PF

    platelet factor

  •  
  • Th

    T helper

  •  
  • TNF-α

    tumour necrosis factor-alpha

  •  
  • VSMC

    vascular smooth muscle cell

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