title: Rho/ROCK signal cascade mediates asymmetric dimethylarginine-induced vascular smooth muscle cells migration and phenotype change.
abstract: Asymmetric dimethylarginine (ADMA) induces vascular smooth muscle cells (VSMCs) migration. VSMC phenotype change is a prerequisite of migration. RhoA and Rho-kinase (ROCK) mediate migration of VSMCs. We hypothesize that ADMA induces VSMC migration via the activation of Rho/ROCK signal pathway and due to VSMCs phenotype change. ADMA activates Rho/ROCK signal pathway that interpreted by the elevation of RhoA activity and phosphorylation level of a ROCK substrate. Pretreatment with ROCK inhibitor, Y27632 completely reverses the induction of ADMA on ROCK and in turn inhibits ADMA-induced VSMCs migration. When the Rho/ROCK signal pathway has been blocked by pretreatment with Y27632, the induction of ERK signal pathway by ADMA is completely abrogated. Elimination of ADMA via overexpression of dimethylarginine dimethylaminohydrolase 2 (DDAH2) and L-arginine both blocks the effects of ADMA on the activation of Rho/ROCK and extra cellular signal-regulated kinase (ERK) in VSMCs. The expression of differentiated phenotype relative proteins was reduced and the actin cytoskeleton was disassembled by ADMA, which were blocked by Y27632, further interpreting that ADMA inducing VSMCs migration via Rho/ROCK signal pathway is due to its effect on the VSMCs phenotype change. Our present study may help to provide novel insights into the therapy and prevention of atherosclerosis.
authors.affiliation: Department of Liver Disease, The Military General Hospital of Beijing PLA, Beijing 100072, China.
authors.forename: Yi-ming
authors.initials: YM
authors.lastname: Zhou
authors.affiliation: Department of Anesthesiology and Critical Care Medicine, School of Medicine, Johns Hopkins University, Baltimore, MD 21205, USA.
authors.forename: Xi
authors.initials: X
authors.lastname: Lan
authors.affiliation: Department of Liver Disease, The Military General Hospital of Beijing PLA, Beijing 100072, China.
authors.forename: Han-bin
authors.initials: HB
authors.lastname: Guo
authors.affiliation: Department of Clinical Laboratory, The Military General Hospital of Beijing PLA, Beijing 100072, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Liver Disease, The Military General Hospital of Beijing PLA, Beijing 100072, China.
authors.forename: Li
authors.initials: L
authors.lastname: Ma
authors.affiliation: Department of Liver Disease, The Military General Hospital of Beijing PLA, Beijing 100072, China.
authors.forename: Jian-biao
authors.initials: JB
authors.lastname: Cao
mesh_terms: D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives* / Q000494:pharmacology; D015415:Biomarkers / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D048430:Cell Shape / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000166:cytology*; D032389:Myocytes, Smooth Muscle / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology; D010641:Phenotype; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects*; D054460:rho-Associated Kinases / Q000378:metabolism*; D020742:rhoA GTP-Binding Protein / Q000378:metabolism*
chemical_list: D015415:Biomarkers; C018524:N,N-dimethylarginine; D001120:Arginine; D054460:rho-Associated Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D020742:rhoA GTP-Binding Protein