JCAD, a gene at the 10p11 coronary artery disease locus, regulates hippo signaling in endothelial cells

Journal article

Objective— 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 (junctional cadherin 5 associated) in endothelial cells. Approach and Results— 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. Conclusions— 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.

Authors: Jones, P; Kaiser, M; Ghaderi Najafabadi, M; Koplev, S; Zhao, Y

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: American Heart Association
• Journal: Arteriosclerosis, Thrombosis, and Vascular Biology
• Volume: 38
• Issue: 8
• Pages: 1711-1722
• Publication date: 2018-05-24
• Acceptance date: 2018-05-09
• DOI: 10.1161/atvbaha.118.310976
• EISSN: 1524-4636
• ISSN: 1079-5642
• Pmid: 29794114
• Language: English
• Keywords: endothelium; atherosclerosis; apoptosis; coronary artery disease; phenotype