Abstract 11570: Targeted Disruption of JCAD/KIAA1462, a Coronary Artery Disease-associated Gene Product, Inhibits Angiogenic Processes in Vitro and in Vivo
Background: 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.
Methods and Results: Cell culture experiments revealed impaired angiogenic ability (WST-1 assay, wound healing, and tube formation) by the knock down of JCAD with siRNA (p<0.05 vs. control siRNA). We generated mice lacking JCAD (JCAD-/-) by gene-targeted deletion of JCAD to address in vivo angiogenic function. JCAD-/- mice did not show differences in development of retinal vasculature. Ex vivo aortic ring model demonstrated impaired neovascularization in aorta from JCAD-/- mice than control wild-type mice (p<0.05). Tumor growth was assessed by monitoring tumor volume after the subcutaneous injection of melanoma cells into the mice. JCAD-/- mice exhibited 45% smaller tumor volume compared with wild-type mice (p<0.001). Histological assessment of tumor exhibited less smooth muscle actin (SMA)-positive neovascularization determined by CD31 staining in tumor of JCAD-/- mice than wild-type mice, indicating that knock-down of JCAD inhibited the vascular maturation in angiogenic process.
Conclusions: These in vitro and in vivo studies suggest that JCAD has a redundant functional role in physiological angiogenesis, but serves an essential role in pathological angiogenic process.
Author Disclosures: T. Hara: None. T. Monguchi: None. M. Akashi: None. N. Iwamoto: None. K. Mori: None. R. Toh: None. Y. Irino: None. M. Shinohara: None. M. Furuse: None. T. Ishida: None. K. Hirata: None.
- © 2015 by American Heart Association, Inc.