Aab Cardiovascular Research Institute, Department of Medicine, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA.
NHC Key Laboratory of Biotechnology of Antibiotics, Institute of Medicinal Biotechnology, Peking Union Medical College and Chinese Academy of Medical Sciences (CAMS), Beijing, China.
Eur Heart J. 2019 Aug 1;40(29):2398-2408. doi: 10.1093/eurheartj/ehz303.
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.
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.
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.
最近的全基因组关联研究（GWAS）已经确定 JCAD 基因座与冠状动脉疾病（CAD）和心肌梗死（MI）的风险相关。然而，候选基因 JCAD 赋予疾病风险的机制仍不清楚。我们研究了 JCAD 是否以及如何影响动脉粥样硬化的发展，这是 CAD 的常见原因。
通过挖掘 Genotype-Tissue Expression（GTEx）数据库中的数据，我们发现 JCAD 基因座与 CAD 相关的风险变异与人类动脉中 JCAD 基因表达的增加有关，提示 JCAD 是候选的 CAD 致病基因。因此，我们生成了全局和内皮细胞（EC）特异性 JCAD 敲除小鼠，并观察到 JCAD 缺乏可减弱载脂蛋白 E 缺陷小鼠的高脂肪饮食诱导的动脉粥样硬化。JCAD 缺乏还改善了内皮依赖性舒张功能。JCAD 耗尽的人冠状动脉内皮细胞的全基因组转录谱分析显示，JCAD 耗尽抑制了 YAP/TAZ 通路的激活以及下游促动脉粥样硬化基因 CTGF 和 Cyr61 的表达。结果，JCAD 缺陷的 EC 对脂多糖（LPS）刺激的单核细胞募集减少。此外，在体外和体内单向层流条件下，EC 中的 JCAD 表达减少。蛋白质组学研究表明，JCAD 通过与肌动蛋白结合蛋白 TRIOBP 相互作用来调节 YAP/TAZ 激活，从而稳定应激纤维形成。最后，我们观察到内皮 JCAD 表达在小鼠和人动脉粥样硬化斑块中增加。
本研究表明，GWAS 确定的 CAD 风险基因 JCAD 促进内皮功能障碍和动脉粥样硬化，从而突出了通过靶向 JCAD 为 CAD 提供新的治疗策略的可能性。
