Abstract 606: Reciprocal Gene-Gene Regulation Between GWAS Genes ADTRP and MIA3 Contributing to Susceptibility of Coronary Artery Disease

Genome-wide association studies (GWAS) have identified >60 genomic loci for coronary artery disease (CAD), including ADTRP (regulator of TFPI and coagulation) and MIA3 (involved in ER trafficking of collagens). In this study, we hypothesized that some GWAS genes form a molecular regulatory network involved in the pathogenesis of CAD. Global microarray analysis showed that ADTRP regulated expression of MIA3 and PIK3R3 encoding the regulatory subunit 3 of PI3K. ADTRP-mediated up-regulation of PIK3R3 activates AKT, resulting in up-regulation of MIA3. Knockdown of ADTRP expression promoted oxidized-LDL-mediated monocyte adhesion to endothelial cell (EC) and transendothelial migration of monocytes, inhibited EC proliferation and migration, and increased apoptosis, which was reversed by expression of constitutively active AKT1, while the over-expression of ADTRP in ECs blunted these processes. Knockdown of MIA3 expression also promoted monocyte adhesion to ECs and transendothelial migration of monocytes. Howeve...