title: Oncological miR-182-3p, a Novel Smooth Muscle Cell Phenotype Modulator, Evidences From Model Rats and Patients.
abstract: 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.
  
  
  
  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.
  
  
  
  miR-182-3p is a novel SMC phenotypic modulator by targeting MYADM.
authors.affiliation: 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.
authors.forename: Lan
authors.initials: L
authors.lastname: Sun
authors.affiliation: 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.).
authors.forename: Yongyi
authors.initials: Y
authors.lastname: Bai
authors.affiliation: 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.).
authors.forename: Rui
authors.initials: R
authors.lastname: Zhao
authors.affiliation: 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.).
authors.forename: Tao
authors.initials: T
authors.lastname: Sun
authors.affiliation: 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.).
authors.forename: Ruihua
authors.initials: R
authors.lastname: Cao
authors.affiliation: 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.).
authors.forename: Fuyu
authors.initials: F
authors.lastname: Wang
authors.affiliation: 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.).
authors.forename: Guorong
authors.initials: G
authors.lastname: He
authors.affiliation: 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.).
authors.forename: Wen
authors.initials: W
authors.lastname: Zhang
authors.affiliation: 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.).
authors.forename: Ying
authors.initials: Y
authors.lastname: Chen
authors.affiliation: 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.
authors.forename: Ping
authors.initials: P
authors.lastname: Ye
authors.affiliation: 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.
authors.forename: Guanhua
authors.initials: G
authors.lastname: Du
mesh_terms: D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives / Q000097:blood / Q000494:pharmacology; D002340:Carotid Artery Diseases / Q000097:blood / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D020212:Carotid Artery Injuries / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002454:Cell Differentiation; D002465:Cell Movement; D049109:Cell Proliferation; D002478:Cells, Cultured; D003324:Coronary Artery Disease / Q000097:blood / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D020869:Gene Expression Profiling / Q000379:methods; D005786:Gene Expression Regulation; D006801:Humans; D008297:Male; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D062806:Myelin and Lymphocyte-Associated Proteolipid Proteins / Q000235:genetics / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D058426:Neointima; D020411:Oligonucleotide Array Sequence Analysis; D010641:Phenotype; D034622:RNA Interference; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D014162:Transfection; D066253:Vascular Remodeling / Q000187:drug effects
chemical_list: C577631:MIRN182 microRNA, rat; C405987:MYADM protein, human; D035683:MicroRNAs; C538984:Mirn182 microRNA, human; C503869:Myadm protein, rat; D062806:Myelin and Lymphocyte-Associated Proteolipid Proteins; C018524:N,N-dimethylarginine; D001120:Arginine; D048049:Extracellular Signal-Regulated MAP Kinases
keywords: asymmetrical dimethylarginine; atherosclerosis; microRNA; myeloid-associated differentiation marker; smooth muscle cell; vascular remodeling