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The novel coronary artery disease risk gene JCAD/KIAA1462 promotes endothelial dysfunction and atherosclerosis
Suowen Xu1, Yanni Xu1,2, Peng Liu1,2
1Aab Cardiovascular Research Institute, Department of Medicine, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA.
Insights
Genome-wide association studies link the JCAD gene to coronary artery disease (CAD) risk. This study shows JCAD promotes atherosclerosis by affecting endothelial cells, suggesting JCAD as a potential therapeutic target for CAD.
Area of Science:
- Cardiovascular Biology
- Molecular Genetics
- Atherosclerosis Research
Background:
- Genome-wide association studies (GWAS) identified the JCAD locus as a risk factor for coronary artery disease (CAD) and myocardial infarction (MI).
- The precise mechanisms by which JCAD contributes to CAD pathogenesis remain largely unknown.
- Understanding JCAD's role is crucial for developing novel therapeutic strategies against atherosclerosis.
Purpose of the Study:
- To investigate the functional role of JCAD in the development of atherosclerosis.
- To elucidate the molecular mechanisms underlying JCAD's contribution to endothelial dysfunction and CAD risk.
Main Methods:
- Analysis of Genotype-Tissue Expression (GTEx) database to correlate CAD risk variants with JCAD expression in arteries.
- Generation of global and endothelial cell (EC)-specific JCAD knockout mice.
- Assessment of atherosclerosis in ApoE-deficient mice fed a high-fat diet.
- Evaluation of endothelium-dependent relaxation.
- Genome-wide transcriptional profiling of JCAD-depleted human coronary artery ECs.
- Proteomics to identify JCAD interacting proteins.
- In vitro and in vivo studies of ECs under laminar flow.
- Analysis of JCAD expression in human and mouse atherosclerotic plaques.
Main Results:
- CAD risk variants at the JCAD locus are associated with increased JCAD expression in human arteries.
- JCAD deficiency in mice attenuated high-fat diet-induced atherosclerosis and improved endothelium-dependent relaxation.
- JCAD depletion in ECs inhibited YAP/TAZ pathway activation and reduced expression of pro-atherogenic genes (CTGF, Cyr61).
- JCAD-deficient ECs exhibited reduced monocyte attraction.
- JCAD interacts with TRIOBP to regulate YAP/TAZ activation via stress fiber stabilization.
- Endothelial JCAD expression is upregulated in atherosclerotic plaques.
Conclusions:
- The GWAS-identified CAD risk gene JCAD promotes endothelial dysfunction and atherosclerosis.
- Targeting JCAD presents a potential new therapeutic strategy for CAD treatment.
Aims:
Recent genome-wide association studies (GWAS) have identified that the JCAD locus is associated with risk of coronary artery disease (CAD) and myocardial infarction (MI). However, the mechanisms whereby candidate gene JCAD confers disease risk remain unclear. We addressed whether and how JCAD affects the development of atherosclerosis, the common cause of CAD.
Methods And Results:
By mining data in the Genotype-Tissue Expression (GTEx) database, we found that CAD-associated risk variants at the JCAD locus are linked to increased JCAD gene expression in human arteries, implicating JCAD as a candidate causal CAD gene. We therefore generated global and endothelial cell (EC) specific-JCAD knockout mice, and observed that JCAD deficiency attenuated high fat diet-induced atherosclerosis in ApoE-deficient mice. JCAD-deficiency in mice also improved endothelium-dependent relaxation. Genome-wide transcriptional profiling of JCAD-depleted human coronary artery ECs showed that JCAD depletion inhibited the activation of YAP/TAZ pathway, and the expression of downstream pro-atherogenic genes, including CTGF and Cyr61. As a result, JCAD-deficient ECs attracted fewer monocytes in response to lipopolysaccharide (LPS) stimulation. Moreover, JCAD expression in ECs was decreased under unidirectional laminar flow in vitro and in vivo. Proteomics studies suggest that JCAD regulates YAP/TAZ activation by interacting with actin-binding protein TRIOBP, thereby stabilizing stress fiber formation. Finally, we observed that endothelial JCAD expression was increased in mouse and human atherosclerotic plaques.
Conclusion:
The present study demonstrates that the GWAS-identified CAD risk gene JCAD promotes endothelial dysfunction and atherosclerosis, thus highlighting the possibility of new therapeutic strategies for CAD by targeting JCAD.
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