A key role for the novel coronary artery disease gene JCAD in atherosclerosis via shear stress mechanotransduction

INTRODUCTION: Genome Wide Association studies have consistently identified an association between coronary artery disease (CAD) and a locus on chromosome 10 containing a single gene, JCAD (formerly KIAA1462). However, little is known about the mechanism by which JCAD could influence the development of atherosclerosis. METHODS AND RESULTS: Vascular function was quantified in subjects with CAD by flow mediated dilatation [FMD] and vasorelaxation responses in isolated blood vessel segments. The JCAD risk allele identified by GWAS was associated with reduced FMD and reduced endothelial-dependent relaxations. To study the impact of loss of Jcad on atherosclerosis, Jcad-/- mice were crossed to an ApoE-/- background and fed a high fat diet from 6 to16 weeks of age. Loss of Jcad did not affect blood pressure or heart rate. However, Jcad-/-ApoE-/- mice developed significantly less atherosclerosis in the aortic root and the inner curvature of the aortic arch. En-face analysis revealed a striking reduction in pro-inflammatory adhesion molecules at sites of disturbed flow on the endothelial cell layer of Jcad-/- mice. Loss of Jcad lead to a reduced recovery perfusion in response to hind limb ischemia, a model of altered in vivo flow. Knock down of JCAD using siRNA in primary human aortic endothelial cells significantly reduced the response to acute onset of flow, as evidenced by reduced phosphorylation of NF-КB, eNOS and Akt. CONCLUSION: The novel CAD gene JCAD promotes atherosclerotic plaque formation via a role in the endothelial cell shear stress mechanotransduction pathway. TRANSLATIONAL PERSPECTIVE: We reveal that JCAD is a novel coronary artery disease susceptibility gene which determines atherosclerosis progression via a role in the endothelial cell shear stress mechanotransduction pathway. Identifying this new role for JCAD in atherosclerotic plaque progression highlights the importance of new coronary artery disease genes that mediate blood flow mechanotransduction in the pathogenesis of coronary artery disease. These genes are potential novel targets for treatments to reduce atherosclerotic plaque formation, independent of established risk factors and biological mechanisms.