Lan Sun1, Yongyi Bai2, Rui Zhao2, Tao Sun2, Ruihua Cao2, Fuyu Wang2, Guorong He2, Wen Zhang2, Ying Chen2, Ping Ye1, Guanhua Du1. 1. From the State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China (L.S., R.Z., G.H., W.Z., Y.C., G.D.); Beijing Key Laboratory of Drug Targets Identification and Drug Screening, Beijing, China (L.S., R.Z., G.H., W.Z., Y.C., G.D.); Department of Geriatric Cardiology, Chinese PLA General Hospital, Beijing, China (Y.B., R.C., P.Y.); Department of Cardiology, Huashan Hospital, Fudan University, Shanghai, China (T.S.); and Department of Neurosurgery, PLA General Hospital, Haidian District, Beijing, China (F.W.). sunhanxing2005@imm.ac.cn duguanhua_imm@sina.com yeping301@sina.com. 2. From the State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China (L.S., R.Z., G.H., W.Z., Y.C., G.D.); Beijing Key Laboratory of Drug Targets Identification and Drug Screening, Beijing, China (L.S., R.Z., G.H., W.Z., Y.C., G.D.); Department of Geriatric Cardiology, Chinese PLA General Hospital, Beijing, China (Y.B., R.C., P.Y.); Department of Cardiology, Huashan Hospital, Fudan University, Shanghai, China (T.S.); and Department of Neurosurgery, PLA General Hospital, Haidian District, Beijing, China (F.W.).
Abstract
OBJECTIVE: Vascular smooth muscle cell (VSMC) phenotype change is a hallmark of vascular remodeling, which contributes to atherosclerotic diseases and can be regulated via microRNA-dependent mechanisms. We recently identified that asymmetrical dimethylarginine positively correlates to vascular remodeling-based diseases. We hypothesized that asymmetrical dimethylarginine induces smooth muscle cell (SMC) phenotypic change via a microRNA-dependent mechanism. APPROACH AND RESULTS: Microarray analysis enabled the identification of downregulation of miR-182-3p in asymmetrical dimethylarginine-treated human aortic artery SMCs. The myeloid-associated differentiation marker (MYADM) was identified as the downstream target of miR-182-3p and implicated to contribute to miR-182-3p knockdown-mediated SMC phenotype change, which was evidenced by the increased proliferation and migration and reduced expression levels of phenotype-related genes in human aortic artery SMCs through the ERK/MAP (extracellular signal-regulated kinase/mitogen-activated protein) kinase-dependent mechanism. When inhibiting MYADM in the presence of miR-182-3p inhibitor or overexpressing MYADM in the presence of pre-miR-182-3p, human aortic artery SMCs were reversed to the differentiation phenotype. In vivo, adeno-miR-182-3p markedly suppressed carotid neointimal formation by using balloon-injured rat carotid artery model, specifically via decreased MYADM expression, whereas adeno-miR-182-3p inhibitor significantly promoted neointimal formation. Atherosclerotic lesions from patients with high asymmetrical dimethylarginine plasma levels exhibited decreased miR-182-3p expression levels and elevated MYADM expression levels. CONCLUSIONS: miR-182-3p is a novel SMC phenotypic modulator by targeting MYADM.
OBJECTIVE: Vascular smooth muscle cell (VSMC) phenotype change is a hallmark of vascular remodeling, which contributes to atherosclerotic diseases and can be regulated via microRNA-dependent mechanisms. We recently identified that asymmetrical dimethylarginine positively correlates to vascular remodeling-based diseases. We hypothesized that asymmetrical dimethylarginine induces smooth muscle cell (SMC) phenotypic change via a microRNA-dependent mechanism. APPROACH AND RESULTS: Microarray analysis enabled the identification of downregulation of miR-182-3p in asymmetrical dimethylarginine-treated human aortic artery SMCs. The myeloid-associated differentiation marker (MYADM) was identified as the downstream target of miR-182-3p and implicated to contribute to miR-182-3p knockdown-mediated SMC phenotype change, which was evidenced by the increased proliferation and migration and reduced expression levels of phenotype-related genes in human aortic artery SMCs through the ERK/MAP (extracellular signal-regulated kinase/mitogen-activated protein) kinase-dependent mechanism. When inhibiting MYADM in the presence of miR-182-3p inhibitor or overexpressing MYADM in the presence of pre-miR-182-3p, human aortic artery SMCs were reversed to the differentiation phenotype. In vivo, adeno-miR-182-3p markedly suppressed carotid neointimal formation by using balloon-injured rat carotid artery model, specifically via decreased MYADM expression, whereas adeno-miR-182-3p inhibitor significantly promoted neointimal formation. Atherosclerotic lesions from patients with high asymmetrical dimethylarginine plasma levels exhibited decreased miR-182-3p expression levels and elevated MYADM expression levels. CONCLUSIONS: miR-182-3p is a novel SMC phenotypic modulator by targeting MYADM.
Authors: Hong S Lu; Ann Marie Schmidt; Robert A Hegele; Nigel Mackman; Daniel J Rader; Christian Weber; Alan Daugherty Journal: Arterioscler Thromb Vasc Biol Date: 2018-10 Impact factor: 8.311