Oncological miR-182, a novel smooth muscle cell phenotype modulator and negatively correlated to pla

• 作 者: SUN Lan ZHAO Rui HE Guo-rong ZHANG Wen YE Ping DU Guan-hua
• 机 构: National center for Pharmaceutical Screening,Chinese Academy of Medical Science and Peking Union Med
• 出 处: 中国药理学会第十三次全国学术大会
• 发表日期: 2015年7期
• 关键词: miRNA vascular smooth muscle ceils phenotype change vascular remodeling coronary

　　Background and Aim Vascular smooth muscle cell (SMC) phenotype change is a hallmark of vascular remodeling, which can be regulated via MicroRNAs (miRNAs)dependent mechanism.We recently identified Asymmetric dimethylarginine (ADMA) positively correlates to vascular remodelingbased diseases.Here, we hypothesized that ADMA induces SMC phenotypic change via a miRNAdependent mechanism.Methods and Results Microarray analysis enabled the identification of 7 deregulated microRNAs in ADMAtreated human aortic artery smooth muscle cells (hASMCs).miR182 was validated by realtimePCR.Isobaric tags for relative and absolute quantitation (iTRAQ) based analysis of the hASMC proteome revealed that transfection of an miR182 inhibitor significantly increased myeloidassociated differentiation marker (MYADM), which was verified using Western blot and reporter activity quantization with the MYADM 3′UTR dualluciferase reporter system, miR182 knockdown further repressed Sprouty2 and enhanced MYADM, leading to ERK/MAP kinasedependent and MYADMdependent hASMC phenotypic change including proliferation, migration and differentiation marker gene expression change.In vivo, adenomiR182 markedly suppressed carotid neointimal formation by using ballooninjured rat carotid artery model, specifically via decreased MYADM expression.Atherosclerotic lesions from patients with high ADMA plasma levels exhibited decreased miR182 expression levels and elevated MYADM expression levels.In patients with coronary heart disease (n =164), the miR182 expression level in plasma was negatively correlated with the plasma ADMA levels.Conclusions miR182 is a novel SMC phenotypic modulator by targeting MYADM and can be a potential therapeutic target combating vascular remodelingassociated diseases.Reduced plasma miR182 levels might be a new predictor of high vascular remodeling risk especially in patient with coronary heart disease.