Identification of a molecular signaling gene-gene regulatory network between GWAS susceptibility genes ADTRP and MIA3/TANGO1 for coronary artery disease.
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.
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.
Chunyan
C
Luo
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.
Fan
F
Wang
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.
Xiang
X
Ren
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.
Tie
T
Ke
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.
Chengqi
C
Xu
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.
Bo
B
Tang
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.
Subo
S
Qin
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.
Yufeng
Y
Yao
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.
Qiuyun
Q
Chen
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.
Qing Kenneth
QK
Wang
D051784:Aryl Hydrocarbon Receptor Nuclear Translocator / Q000096:biosynthesis* / Q000235:genetics; D050197:Atherosclerosis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D003324:Coronary Artery Disease / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D005786:Gene Expression Regulation / Q000235:genetics; D053263:Gene Regulatory Networks; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D056945:Hep G2 Cells; D061307:Human Umbilical Vein Endothelial Cells / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000096:biosynthesis / Q000235:genetics; D015398:Signal Transduction
C568706:ADTRP protein, human; C497396:ARNT protein, human; D008565:Membrane Proteins; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator; D019869:Phosphatidylinositol 3-Kinases; C523442:PIK3R3 protein, human
ADTRP; AKT; ApoB; Collagen VII; Coronary artery disease (CAD); MIA3 (TANGO1); Myocardial infarction (MI); PI3K