JCAD: a new GWAS target to reduce residual cardiovascular risk?

Graphical Abstract

Graphical Abstract.

Divergent spectrum of the mechanisms of residual cardiovascular risk linked to JCAD that could be therapeutically targeted in the future.

This editorial refers to ‘JCAD promotes arterial thrombosis through PI3K/Akt modulation: a translational study’, by L. Liberale et al., https://doi.org/10.1093/eurheartj/ehac641.

In spite of major improvements in the management of cardiovascular risk, the incidence of acute cardiovascular events, including myocardial infarctions and strokes, remains high. This residual cardiovascular risk, which persists despite optimal improvements of major lipid and other cardiovascular risk factors, reflects in part the contributions of as yet unidentified biological pathways and processes that are not targeted by current therapies.¹ Large clinical trials in recent years have shown that targeting residual cardiovascular risk with anticoagulant (COMPASS), anti-inflammatory (CANTOS and LODOCO),² or HDL-targeted therapies can significantly reduce the risk of major cardiovascular events or death by an additional 15–22%.³ Thus, at least three mechanisms of residual cardiovascular risk, i.e. lipid, thrombotic, and inflammatory,¹ appear to be valid therapeutic targets.⁴ However, there remains an urgent need to identify therapies that would comprehensively target these and other novel mechanisms. In this regard, a large number of new ‘hits’ from coronary artery disease (CAD) genome-wide association studies (GWAS) offer the potential for identifying entirely new targetable mechanisms in CAD pathogenesis, by focusing on those GWAS hits that are not associated with known risk factors, such as lipid metabolism. However, even if the causal allele associated with CAD risk can be identified, the mechanisms linking the putative new gene to CAD are usually obscure and need to be understood in order to guide translation towards clinical benefit.

JCAD (junctional cadherin 5 associated, also known as KIAA1462) is a new potential therapeutic target in cardiovascular disease. Numerous GWAS indicate that JCAD is a risk locus for coronary artery disease.^5,6 Mechanistic studies demonstrated that in endothelial cells (ECs), JCAD interacts with LATS2 (large tumour suppressor kinase 2) and negatively regulates Hippo signalling, leading to increased activity of YAP (yes-associated protein), the transcriptional effector of the pathway.^7,8 JCAD expression increases in the endothelial layer in experimental atherosclerosis in mice.^8,9 Moreover, the CAD-associated lead variant, rs2487928, is associated with the expression of JCAD in arteries, including atherosclerotic arteries, with the protective allele associated with reduced expression of JCAD.⁷ This has also been observed using Genotype-Tissue Expression (GTEx) database analysis.⁹

 

The role of JCAD in atherosclerosis

These observations prompted the generation and study of global and EC-specific JCAD knockout mice.^8,9 These showed that JCAD deficiency protects from high-fat diet-induced endothelial dysfunction and attenuates high-fat diet-induced atherosclerosis in ApoE-deficient mice.^7,8 JCAD appears to be part of mechanotransduction-dependent mechanisms of atherosclerosis, as unidirectional laminar flow decreases JCAD expression. Proteomics studies suggest that JCAD regulates YAP/TAZ activation by interacting with the actin-binding protein TRIOBP, thereby stabilizing stress fibre formation. In atherosclerotic phenotypes, JCAD is involved in the transmission of RhoA-mediated signals into the Hippo pathway and requires LATS2.

JCAD in vascular inflammation

Another fundamental mechanism through which JCAD appears to exert its antiatherosclerotic effects is the modulation of vascular inflammation. Loss of JCAD is linked to a striking reduction in the expression of proinflammatory adhesion molecules on EC membranes at sites of disturbed flow.⁸ Such a link between disturbed flow, constituting one of the key local stimuli for developing atherosclerotic plaques, is essential.¹⁰ This is also observed in response to other stimuli that induce endothelial dysfunction, such as lipopolysaccharide (LPS)-dependent inflammation, as JCAD-deficient ECs attract fewer monocytes in response to such proinflammatory stimuli.⁹

The role of JCAD in thrombosis

While known effects on endothelial biology could explain the role of JCAD in CAD, the effects of JCAD in an acute setting of cardiovascular events remained unknown. The study by Liberale et al.¹¹ published in this issue of the European Heart Journal addresses the importance of JCAD from a different angle. By focusing on its relevance to thrombosis, the authors provided mechanistic insights into the possible role of JCAD in acute vascular events. Clinically, they demonstrate that circulating plasma levels of JCAD are increased in ST-segment elevation myocardial infarction (STEMI) compared with chronic coronary syndrome (CCS). The observation that JCAD is potentially present in human plasma raises the questions of where it is released from, by what mechanisms, and in response to which stimuli—but offers the prospect of clinical studies where plasma JCAD levels may be a useful biomarker, measured in different clinical settings, and in response to therapeutic interventions. More validation of JCAD as a possible biomarker is, however, necessary before drawing unequivocal conclusions. To investigate the role of JCAD mechanistically, the authors used a model of photochemically induced endothelial injury to trigger arterial thrombosis which was inhibited in mice lacking Jcad.

While the most apparent mechanism, related to platelet aggregation, does not seem to be modulated by JCAD, the authors investigated activation of the coagulation cascade and increased fibrinolysis. Through in vitro silencing studies, they found that JCAD is involved in regulating both tissue factor (TF) and plasminogen activator inhibitor-1 (PAI-1) expression in human ECs. Importantly, in contrast to the regulation of endothelial dysfunction and atherosclerosis per se, the key mechanism involved in JCAD-dependent regulation of thrombogenicity is largely LATS2 independent. These effects are mediated by the activation of PI3K/Akt, known to down-regulate procoagulant expression. The authors postulate direct interaction between Akt and JCAD. This is important as it identifies potentially important pathways in endothelial function and atherosclerosis, as Akt-dependent mechanisms are fundamental in this process. Lastly, they provide translational support to these findings in a patient population in whom JCAD plasma levels appear to be correlated with both TF and PAI-1 levels.

In summary, the work by Liberale et al. suggests a potential novel therapeutic role for JCAD inhibition in acute cardiovascular events dependent on increased arterial thrombogenicity. This is important, as considering the effects of JCAD on vascular dysfunction, thrombogenicity, and inflammation, it may serve as an essential candidate for effective targeting of divergent mechanisms of residual cardiovascular risk (Graphical Abstract). Achieving this will require the development of specific pharmacological JCAD inhibitors and an understanding of its broader physiological functions to ensure the safety of such approaches. The broad effects of JCAD reported for other non-classical risk factors of CVD, such as non-alcoholic steatohepatitis,¹² may make it an even stronger candidate for future therapeutic approaches. JCAD is an exciting exemplar of how a previously unknown CAD GWAS ‘hit’ can reveal new insights into CAD pathogenesis, and the potential for new therapeutic targets to address residual cardiovascular risk.

Funding

T.J.G. is funded by the European Research Council [ERC and InflammaTENSION; ERC-CoG-726318], British Heart Foundation [FS/14/49/30838, RE/18/5/34216 and FS/4yPhD/F/20/34127A], European Commission and the National Centre for Research and Development (NCBR; Poland) [ERA-CVD/Gut-brain/8/2021; ERA-CVD/JTC2020/25/ImmuneHyperCog/2022]; K.M.C. is supported by the British Heart Foundation [CH/16/1/32013].