期刊
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE
卷 1863, 期 6, 页码 1640-1653出版社
ELSEVIER
DOI: 10.1016/j.bbadis.2017.03.010
关键词
Coronary artery disease (CAD); Myocardial infarction (MI); ADTRP; MIA3 (TANGO1); AKT; PI3K; Collagen VII; ApoB
资金
- NHLBI NIH HHS [R01 HL126729, R01 HL121358] Funding Source: Medline
Coronary artery disease (CAD) is the leading cause of death worldwide. GWAS have identified > 50 genomic loci for CAD, including ADTRP and MIA3/TANGOI. However, it is important to determine whether the GWAS genes form a molecular network. In this study, we have uncovered a novel molecular network between ADTRP and MIA3/TANGOI for the pathogenesis of CAD. We showed that knockdown of ADTRP expression markedly down-regulated expression of MIA3/TANGOI. Mechanistically, ADTRP positively regulates expression of PIK3R3 encoding the regulatory subunit 3 of PI3K, which leads to activation of AKT, resulting in up-regulation of MIA3/TANGOI. Both ADTRP and MIA3/TANGOI are involved in endothelial cell (EC) functions relevant to atherosclerosis. Knockdown of ADTRP expression by siRNA promoted oxidized-LDL-mediated monocyte adhesion to ECs and transendothelial migration of monocytes, inhibited EC proliferation and migration, and increased apoptosis, which was reversed by expression of constitutively active AKT1 and MIA3/TANGO1 overexpression, while the over -expression of ADTRP in ECs blunted these processes. Knockdown of MIA3/TANG01 expression also promoted monocyte adhesion to ECs and transendothelial migration of monocytes, and vice versa for overexpression of MIA3/TANGOI. We found that ADTRP negatively regulates the levels of collagen VII and ApoB in HepG2 and endothelial cells, which are downstream regulatory targets of MIA3/TANGOI. In conclusion, we have uncovered a novel molecular signaling pathway for the pathogenesis of CAD, which involves a novel gene -gene regulatory network. We show that ADTRP positively regulates PIK3R3 expression, which leads to activation of AKT and up-regulation of MIA3/TANGOI, thereby regulating endothelial cell functions directly relevant to atherosclerosis.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据