JCAD, a Gene at the 10p11 Coronary Artery Disease Locus, Regulates Hippo Signaling in Endothelial Cells.
JCAD, a Gene at the 10p11 Coronary Artery Disease Locus, Regulates Hippo Signaling in Endothelial Cells.
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DOI：
10.1161/atvbaha.118.310976
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发表时间：
2018-08
期刊：
影响因子：
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通讯作者：
Webb TR
中科院分区：
文献类型：
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作者：
Jones PD;Kaiser MA;Ghaderi Najafabadi M;Koplev S;Zhao Y;Douglas G;Kyriakou T;Andrews S;Rajmohan R;Watkins H;Channon KM;Ye S;Yang X;Björkegren JLM;Samani NJ;Webb TR
通过全基因组关联研究，大量基因位点与冠状动脉疾病（CAD）风险相关，然而，对于大多数基因位点，其潜在的生物学机制尚不清楚。确定受这些基因座影响的分子途径和细胞过程将为CAD病理生理学提供新的见解，并可能导致新的治疗方法。10p11.23位点的cad相关变异体在编码内皮连接蛋白的JCAD中下降，然而，其在内皮细胞中的分子功能尚不清楚。在这项研究中，我们描述了JCAD在内皮细胞中的分子作用。我们发现内皮细胞中的JCAD敲低会影响与动脉粥样硬化相关的关键表型，包括增殖、迁移、凋亡、管形成和单核细胞结合。我们证明，JCAD与LATS2（大肿瘤抑制激酶2）相互作用，负调控Hippo信号传导，导致YAP （yes相关蛋白）活性增加，YAP是该途径的转录效应因子。我们还通过双siRNA敲低表明，JCAD敲低引起的表型需要LATS2，并且JCAD参与rhoa介导的信号传递到Hippo通路。在人体组织中，我们发现cad相关的铅变体rs2487928与动脉（包括动脉粥样硬化动脉）中JCAD的表达相关。跨疾病相关组织的基因共表达分析证实了我们的表型发现，并支持JCAD和Hippo信号之间的联系。我们的研究结果表明，JCAD负调控内皮细胞中的Hippo信号，我们认为JCAD通过介导YAP活性和内皮功能障碍来促进动脉粥样硬化。
A large number of genetic loci have been associated with risk of coronary artery disease (CAD) through genome-wide association studies, however, for most loci the underlying biological mechanism is unknown. Determining the molecular pathways and cellular processes affected by these loci will provide new insights into CAD pathophysiology and may lead to new therapies. The CAD-associated variants at 10p11.23 fall in JCAD, which encodes an endothelial junction protein, however, its molecular function in endothelial cells is not known. In this study we characterize the molecular role of JCAD in endothelial cells. We show that JCAD knockdown in endothelial cells affects key phenotypes related to atherosclerosis including proliferation, migration, apoptosis, tube formation and monocyte binding. We demonstrate that JCAD interacts with LATS2 (large tumor suppressor kinase 2) and negatively regulates Hippo signaling leading to increased activity of YAP (Yes-associated protein), the transcriptional effector of the pathway. We also show by double siRNA knockdown that the phenotypes caused by JCAD knockdown require LATS2 and that JCAD is involved in transmission of RhoA-mediated signals into the Hippo pathway. In human tissues, we find that the CAD-associated lead variant, rs2487928, is associated with expression of JCAD in arteries, including atherosclerotic arteries. Gene co-expression analyses across disease-relevant tissues corroborate our phenotypic findings and support the link between JCAD and Hippo signaling. Our results show that JCAD negatively regulates Hippo signaling in endothelial cells and we suggest that JCAD contributes to atherosclerosis by mediating YAP activity and contributing to endothelial dysfunction.