Targeted Disruption of JCAD (Junctional Protein Associated With Coronary Artery Disease)/KIAA1462, a Coronary Artery Disease-Associated Gene Product, Inhibits Angiogenic Processes In Vitro and In Vivo.

OBJECTIVE:Recent genome-wide association studies newly identified the human KIAA1462 gene as a new locus for coronary artery disease. However, the function of the gene product, named JCAD (junctional protein associated with coronary artery disease), is unknown. Because JCAD is expressed at cell-cell junctions in endothelial cells, we hypothesized and tested whether JCAD regulates angiogenic processes in vitro and in vivo. APPROACH AND RESULTS:Cell culture experiments revealed impaired angiogenic ability (proliferation, migration, and cord formation) by the knockdown of JCAD with siRNA (P<0.05 versus control siRNA). We have generated mice lacking JCAD (mKIAA1462^-/-) by gene-targeted deletion of JCAD to address in vivo angiogenic function. mKIAA1462^-/- mice did not show morphological differences in development of retinal vasculature. Ex vivo aortic ring model demonstrated impaired neovascularization in aorta from mKIAA1462^-/- mice than control wild-type mice (P<0.05). Tumor growth was assessed by monitoring tumor volume after the subcutaneous injection of melanoma, LLC (Lewis lung carcinoma), and E0771 cells into the mice. mKIAA1462^-/- mice exhibited significantly smaller tumor volume compared with wild-type mice (P<0.001). Histological assessment of the tumor exhibited less smooth muscle actin-positive neovascularization determined by CD31-positive vascular structure in tumor of mKIAA1462^-/- mice than wild-type mice, indicating that knockdown of JCAD inhibited the vascular maturation in pathological angiogenic process. CONCLUSIONS:These in vitro and in vivo studies suggest that JCAD has a redundant functional role in physiological angiogenesis but serves a pivotal role in pathological angiogenic process after birth.

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