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Biochim Biophys Acta Mol Basis Dis. 2017 Jun;1863(6):1640-1653. doi: 10.1016/j.bbadis.2017.03.010. Epub 2017 Mar 21.

Identification of a molecular signaling gene-gene regulatory network between GWAS susceptibility genes ADTRP and MIA3/TANGO1 for coronary artery disease.

Author information

1
The Key Laboratory of Molecular Biophysics of the Ministry of Education, College of Life Science and Technology, Center for Human Genome Research, Cardio-X Institute, Huazhong University of Science and Technology, Wuhan 430074, Hubei Province, PR China.
2
Center for Cardiovascular Genetics, Department of Molecular Cardiology, Lerner Research Institute, Department of Cardiovascular Medicine, Cleveland Clinic, Cleveland, OH 44195, USA; Department of Molecular Medicine, Department of Genetics and Genome Science, Case Western Reserve University, Cleveland, OH 44195, USA.
3
Center for Cardiovascular Genetics, Department of Molecular Cardiology, Lerner Research Institute, Department of Cardiovascular Medicine, Cleveland Clinic, Cleveland, OH 44195, USA; Department of Molecular Medicine, Department of Genetics and Genome Science, Case Western Reserve University, Cleveland, OH 44195, USA. Electronic address: chenq3@ccf.org.
4
The Key Laboratory of Molecular Biophysics of the Ministry of Education, College of Life Science and Technology, Center for Human Genome Research, Cardio-X Institute, Huazhong University of Science and Technology, Wuhan 430074, Hubei Province, PR China; Center for Cardiovascular Genetics, Department of Molecular Cardiology, Lerner Research Institute, Department of Cardiovascular Medicine, Cleveland Clinic, Cleveland, OH 44195, USA; Department of Molecular Medicine, Department of Genetics and Genome Science, Case Western Reserve University, Cleveland, OH 44195, USA. Electronic address: qkwang@hust.edu.cn.

Abstract

Coronary artery disease (CAD) is the leading cause of death worldwide. GWAS have identified >50 genomic loci for CAD, including ADTRP and MIA3/TANGO1. 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/TANGO1 for the pathogenesis of CAD. We showed that knockdown of ADTRP expression markedly down-regulated expression of MIA3/TANGO1. 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/TANGO1. Both ADTRP and MIA3/TANGO1 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/TANGO1 expression also promoted monocyte adhesion to ECs and transendothelial migration of monocytes, and vice versa for overexpression of MIA3/TANGO1. 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/TANGO1, thereby regulating endothelial cell functions directly relevant to atherosclerosis.

KEYWORDS:

ADTRP; AKT; ApoB; Collagen VII; Coronary artery disease (CAD); MIA3 (TANGO1); Myocardial infarction (MI); PI3K

PMID:
28341552
PMCID:
PMC5616168
DOI:
10.1016/j.bbadis.2017.03.010
[Indexed for MEDLINE]
Free PMC Article

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