Abstract

Endoplasmic reticulum (ER) and mitochondria are crucial organelles for cell homeostasis and alterations of these organelles have been implicated in cardiovascular disease. However, their roles in abdominal aortic aneurysm (AAA) pathogenesis remain largely unknown. In a recent issue of Clinical Science, Navas-Madronal et al. ((2019), 133(13), 1421–1438) reported that enhanced ER stress and dysregulation of mitochondrial biogenesis are associated with AAA pathogenesis in humans. The authors also proposed that disruption in oxysterols network such as an elevated concentration of 7-ketocholestyerol in plasma is a causative factor for AAA progression. Their findings highlight new insights into the underlying mechanism of AAA progression through ER stress and dysregulation of mitochondrial biogenesis. Here, we will discuss the background, significance of the study, and future directions.

Abdominal aortic aneurysm (AAA) is a pathological condition of permanent dilatation of the aorta (defined as a focal dilatation of 50 percent greater than normal average diameter of an aorta) that is potentially fatal upon rupture [1]. While participation of several mechanisms including chronic inflammation, oxidative stress, and activation of metalloproteinases at the arterial wall have been implicated in AAA, no pharmacological therapy has been validated to prevent AAA progression or rupture [2]. Therefore, it is important to advance the understanding of the pathogenesis of AAA.

Mitochondrial biogenesis, the process by which cells increase mitochondrial mass, is involved in the control of cell metabolism, signal transduction, and regulation of mitochondrial reactive oxygen species (ROS) production [3]. While the regulation of mitochondrial biogenesis involves organization of numerous transcriptional networks, there are critical factors controlling these processes, which include peroxisome proliferator-activated receptor co-activator 1 α (PGC1α) and its downstream targets: nuclear factor erythroid 2-related factor 2 (NRF2) and mitochondrial transcription factor A (TFAM) which coordinately stimulate mitochondrial biogenesis [4]. It has been demonstrated that impaired mitochondrial biogenesis is a common feature of myocardial hypertrophy and end-stage ischemic heart failure [5,6]. Dysregulation of mitochondrial translation, which is required for biogenesis, causes cytoplasmic protein aggregates, and interrupts interorganellar protein homeostasis (proteostasis) [7].

Endoplasmic reticulum (ER) is a key site where proteins are synthesized, folded, and prepared for trafficking [8]. ER stress occurs when the protein-folding demand exceeds the protein-folding capacity leading to enhancement in protein misfolding [9]. Once misfolded proteins accumulate above a critical threshold, a highly conserved intracellular signaling pathway called unfolded protein response (UPR) is triggered (BOX 1) to restore protein homeostasis (proteostasis). However, if protein misfolding is not resolved effectively, chronic UPR results in inflammation, production of ROS, and the sequential cascade of mitochondria-driven apoptosis to eliminate the dysfunctional cell population [10]. Moreover, protein misfolding and aggregation can lead to proteotoxicity/proteopathy and subsequent organ/cell dysfunctions [11]. Although growing evidence suggests that ER stress and impaired mitochondrial biogenesis play causal roles in cardiovascular diseases [12,13], its potential contribution to the AAA pathogenesis has not been fully elucidated.

BOX 1
Unfolded protein response

ER stress response is initiated by a variety of cellular insults, including oxidative stress. To resolve this, the specific transcriptional response pathways termed as ER unfolded protein response (ERUPR) are initiated via binding of unfolded/misfolded proteins to glucose-regulated protein 78 (Grp78), which enhances protein folding capacity, slows protein synthesis, and eliminates dysfunctional protein aggregates. However, if protein misfolding is not resolved effectively, chronic ERUPR results in inflammation, production of ROS, and causes mitochondrial dysfunction and apoptosis.

In volume 133 issue 13 of Clinical Science, Navas-Madronal et al. [14] have demonstrated enhanced expression of ER stress markers and alterations in mitochondrial biogenesis, autophagy, apoptosis, and the oxysterol profiles in AAA patients. The authors found that the mRNA expressions of inositol requiring enzyme 1 (IRE1), X-binding protein 1 (XBP-1), and activating transcription factor 6 (ATF6) in patient aortas with AAA were higher compared with those in healthy donors. Moreover, protein expressions of three ER stress markers, XBP-1, cleaved ATF6, and CCAAT/enhancer-binding protein (C/EBP) homologous protein (CHOP) were also enhanced specifically in vascular smooth muscle cells (VSMCs) in AAA. In line with these results, recent studies have shown that ER stress may play a key role in AAA pathology [15–17]. Therefore, inhibition of ER stress could be a potential therapeutic target to prevent AAA progression and rupture.

Under chronic ER stress, sustained activating transcription factor 4 (ATF4) expression induces autophagy as well as apoptotic response through CHOP activation [18]. It is also known that CHOP plays a central role in ER stress-induced apoptosis through activations of caspase family proteins including cleaved caspase 3 [19]. Several studies have described that autophagy [20–22] and apoptosis [23–27] of VSMCs are involved in AAA in animal models and humans. Consistent with these studies, the authors observed that the enhanced protein expressions of autophagy markers, microtubule-associated protein 1 light chain 3 α (LC3), beclin-1, and p62/Sequestosome 1 (SQSTM1), in the aorta of AAA patients were associated with increased protein expressions of apoptosis markers, CHOP, and cleaved caspase 3. Also, they found that apoptotic cells were increased in aneurysmatic walls compared with those of healthy donors assessed by terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) assay. Because ER stress can induce ROS production and vice versa [28], the authors analyzed mRNA expressions of ROS markers, and found the increased expressions of NADPH oxidase 2 (NOX2) and p22phox mRNA levels in AAA samples, indicating that general ROS production was up-regulated in aortas of AAA patients. Furthermore, they revealed that mitochondrial ROS production was enhanced in aortas of AAA patients as evidenced by Mitosox staining. These findings are in agreement with previous reports in animal models describing that mitochondrial ROS is a potential determinant for AAA [29–31]. However, the detection of ROS is inherently difficult to assess accurately because of a very short half-life of ROS, non-specific reactions, and artifacts [32]. In particular, mitochondrion-targeted dihydroethidium, MitoSOX form fluorescent ethidium via non-specific redox reactions, though this can be distinguished by high performance liquid chromatography [33]. MitoSox is also light sensitive, prone to auto-oxidation, and influenced by cellular uptake. Thus, the specificity of MitoSox to detect mitochondrial ROS has recently been called into question [34]. In conjunction with specificity issues, MitoSox and many other mitochondrial ROS probes utilize lipophilic triphenylphosphonium cations (TPP) to target mitochondrial membranes, which affect mitochondrial metabolism. Accordingly, for alternative in vitro assessment of mitochondrial ROS, genetically encoding probes or small-molecule probes which include a mitochondria localization sequence may yield more accurate results [35]. Mitochondria-targeted mass spectrometric probe MitoB was recently developed to assess mitochondrial ROS in living animals and cells [36]. MitoB accumulates rapidly within the mitochondria and is irreversibly converted into phenol MitoP, proportionate to the local H2O2 concentration [37]. In addition, mitoNeoD has been recently developed for selective measurement of mitochondrial superoxide in vitro and in vivo [38]. Further research is needed to validate the association of mitochondrial ROS in pathogenesis of AAA.

Mitochondria and ER are tightly connected, and they are major sources of ROS [39]. Although there is accumulating evidence highlighting the importance of the interaction between mitochondria and ER for both cardiac and vascular tissue physiologies, only limited reports have investigated a specific role in cardiovascular pathologies [40]. Therefore, the authors next asked whether alterations in mitochondrial biogenesis were associated with ER stress in AAA pathology. They evaluated the ratios of the mRNA expressions of mitochondrial cytochrome b and cytochrome c vs. that of β-actin as indicators of mitochondrial abundance, and found the reduced ratios in AAA samples, suggesting the negative regulation in mitochondrial biogenesis. In support of these findings, the mRNA expressions of mitochondrial biogenesis markers, PGC1α, NRF2, and TFAM, were down-regulated in AAA samples. Similar findings have been reported in human and mouse AAA [41]. However, further studies are needed to determine whether the alterations of mitochondrial biogenesis play a causative role in AAA pathology.

In addition, many other questions remain unanswered. What is the major contributing factor in the alterations of mitochondrial biogenesis in AAA? Which is more important for AAA pathologies, mitochondrial abundance/quantity, or the mitochondrial function/quality? Do balance of mitochondrial dynamics (fusion and fission) or mitophagy contribute to AAA? Do distribution changes of mitochondria in the cells (perinuclear or diffuse mitochondria) and/or interaction between mitochondria and ER play a role? Specifically, genetic and/or pharmacological techniques using molecules that are related to mitochondrial biogenesis, dynamics and quality control could help resolve these questions [40,42,43]. For instance, conditional transgenic mice to manipulate fission (Drp1), fusion (Mfn1/Mfn2), or both have been developed and tested for cardiac functions [42].

One of the novel elements of the study is that the authors have reported that altered cholesterol metabolism was associated in AAA pathogenesis as evidenced by increased 7-ketocholesterol (7-KC), a major oxidation product of cholesterol [44], levels in plasma of AAA patients. 7-KC is abundant in human atherosclerotic plaques [45] and is known to be involved in apoptosis, ER stress and oxidative stress in VSMCs [46,47]. Thus, the authors further asked whether 7-KC induces vascular damage associated with their human AAA findings. Indeed, human VSMCs incubated with 7-KC showed increased apoptotic cells as evidenced by flow cytometry. Also, they found that 7-KC stimulation in VSMCs might result in decreased mitochondrial biogenesis, as shown by decreased mRNA levels of PGC1α and TFAM. In contrast, the mRNA expressions of the ER stress markers, IRE1, ATF6, ATF4, and CHOP were increased in 7-KC-induced VSMCs. The authors also found that 7-KC induced the enhancement of NOX2 mRNA expression. These potentially detrimental effects by 7-KC were attenuated by pretreatment with an antioxidant, Tempol or N-acetyl cysteine. Intriguingly, mRNA levels of CHOP and matrix metalloproteinase 2 (MMP2), an important determinant of AAA progression [48], in VSMCs induced by 7-KC were further augmented by co-stimulation with angiotensin II, a potent vasoconstrictor and a predicted mediator that leads to aneurysm formation in humans [49]. In wild-type mice, Ang II infusion does not induce AAA with high incidence [50]. Therefore, Ang II infusion in mice has been combined with hyperlipidemic backgrounds (ApoE−/− or LDL receptor−/−) [51] or co-treatment with β-aminopropionitrile (BAPN) administration [52–55]. Because 7-KC could be a major determinant for ER stress, ROS generation, and reduced mitochondrial biogenesis in AAA, it would be interesting to evaluate if there is a synergistic effect of Ang II infusion and 7-KC administration on AAA incidence or development in mice.

In summary, the present study performed by Madronal et al. [14] highlights new insights into the underlying mechanism of AAA progression through ER stress and dysregulation of mitochondrial biogenesis (Figure 1). In addition, the authors propose that disruption in oxysterols network such as an elevated concentration of 7-KC in plasma is a causative factor for AAA progression in humans. Limitations of the present study include inherent restrictions of the work using human samples and a mechanistic confirmation based solely in a culture model. Therefore, further studies using well-characterized animal models of AAA combined with specifically influencing ER stress via modalities such as the ERAI transgenic mouse model which shows ER stress-dependent splicing XBP-1 [56] are needed to clarify the underlying molecular mechanisms of ER stress in AAA progression. Taken together, better understanding of how ER stress is involved in AAA pathogenesis may help to develop novel therapeutic strategies.

Cellular mechanisms contributing to pathophysiology of AAA

Figure 1
Cellular mechanisms contributing to pathophysiology of AAA

(A) Schematic diagram illustrating AAA circulating factors and cell types involved. (B) 7-KC and angiotensin II (AngII) induce immune cell activation and VSMC oxidative stress, leading to ER stress signaling and mitochondrial dysfunction. 7-KC and Ang II also mediate increased NOX2 and decreased antioxidant capacity of p22phox and NOX4, subsequent apoptosis and vascular remodeling. At the ER surface, nascent polypeptides are properly folded by chaperones such as glucose-regulated protein 78 (Grp78). When oxidative stress or protein misfolding increases, Grp78 detaches from transmembrane signaling molecules to initiate UPR effectors. Among them, IRE1 and ATF6 activation lead to downstream transcription regulated by spliced XBP-1 and cleaved ATF6, respectively, to enhance expression of protein chaperones, inhibition of protein synthesis and stimulation of autophagy to maintain proteostasis. Stress-induced ERUPR results in increased HSPA5, CREDL2, CHOP, ATF6 cleavage, IRE1, sXBP1, and ER-associated protein degradation (ERAD) mediator SEL1L. SEL1L, an adaptor protein for the ubiquitin ligase Hrd mediates proteasomal degradation of misfolded proteins within the ER. Increased ER stress and oxidative damage leads to decreased mitochondrial biogenesis factors TFAM, PCG1α, NRF1, while mitophagy alterations were observed by lower DRP1, higher Beclin-1, LC3BII and p62 in human AAA. Overall progression of AAA may depend on these cellular factors, representing new therapeutic targets for patients.

Figure 1
Cellular mechanisms contributing to pathophysiology of AAA

(A) Schematic diagram illustrating AAA circulating factors and cell types involved. (B) 7-KC and angiotensin II (AngII) induce immune cell activation and VSMC oxidative stress, leading to ER stress signaling and mitochondrial dysfunction. 7-KC and Ang II also mediate increased NOX2 and decreased antioxidant capacity of p22phox and NOX4, subsequent apoptosis and vascular remodeling. At the ER surface, nascent polypeptides are properly folded by chaperones such as glucose-regulated protein 78 (Grp78). When oxidative stress or protein misfolding increases, Grp78 detaches from transmembrane signaling molecules to initiate UPR effectors. Among them, IRE1 and ATF6 activation lead to downstream transcription regulated by spliced XBP-1 and cleaved ATF6, respectively, to enhance expression of protein chaperones, inhibition of protein synthesis and stimulation of autophagy to maintain proteostasis. Stress-induced ERUPR results in increased HSPA5, CREDL2, CHOP, ATF6 cleavage, IRE1, sXBP1, and ER-associated protein degradation (ERAD) mediator SEL1L. SEL1L, an adaptor protein for the ubiquitin ligase Hrd mediates proteasomal degradation of misfolded proteins within the ER. Increased ER stress and oxidative damage leads to decreased mitochondrial biogenesis factors TFAM, PCG1α, NRF1, while mitophagy alterations were observed by lower DRP1, higher Beclin-1, LC3BII and p62 in human AAA. Overall progression of AAA may depend on these cellular factors, representing new therapeutic targets for patients.

Funding

This work was supported by the NIH [grant number RO1 HL 128324, HL133248, DK111024 (to S.E.)]; the NIH Predoctoral Fellowship [grant number F30HL146006 (to H.A.C.)]; the American Heart Association Predoctoral Fellowship [grant number 19PRE34430037 (to H.A.C.)]; and the JSPS KAKENHI [grant number 18KK0437 (to M.M.)].

Competing Interests

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

Abbreviations

     
  • AAA

    abdominal aortic aneurysm

  •  
  • apoE

    apolipoprotein E

  •  
  • ATF4

    activating transcription factor 4

  •  
  • ATF6

    activating transcription factor 6

  •  
  • ERAI

    ER stress-activated indicator

  •  
  • CHOP

    C/EBP homologous protein

  •  
  • ER

    endoplasmic reticulum

  •  
  • IRE1

    inositol requiring enzyme 1

  •  
  • NOX2

    NADPH oxidase 2

  •  
  • NRF2

    nuclear factor erythroid 2-related factor 2

  •  
  • PGC1α

    peroxisome proliferator-activated receptor co-activator 1 α

  •  
  • ROS

    reactive oxygen species

  •  
  • SQSTM1

    Sequestosome 1

  •  
  • TFAM

    mitochondrial transcription factor A

  •  
  • UPR

    unfolded protein response

  •  
  • VSMC

    vascular smooth muscle cell

  •  
  • XBP-1

    X-binding protein 1

  •  
  • 7-KC

    7-ketocholesterol

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