Sun Lan, Bai Yongyi, Zhao Rui, Sun Tao, Cao Ruihua, Wang Fuyu, He Guorong, Zhang Wen, Chen Ying, Ye Ping, Du Guanhua
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.).
Arterioscler Thromb Vasc Biol. 2016 Jul;36(7):1386-97. doi: 10.1161/ATVBAHA.115.307412. Epub 2016 May 19.
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.
血管平滑肌细胞（VSMC）表型改变是血管重塑的一个标志，它促成动脉粥样硬化疾病，并且可以通过微小RNA依赖的机制进行调节。我们最近发现不对称二甲基精氨酸与基于血管重塑的疾病呈正相关。我们假设不对称二甲基精氨酸通过微小RNA依赖的机制诱导平滑肌细胞（SMC）表型改变。
微阵列分析能够鉴定出在不对称二甲基精氨酸处理的人主动脉平滑肌细胞中miR-182-3p表达下调。髓样相关分化标志物（MYADM）被鉴定为miR-182-3p的下游靶点，并被认为促成了miR-182-3p敲低介导的SMC表型改变，这通过人主动脉平滑肌细胞中增殖和迁移增加以及表型相关基因表达水平降低得以证明，其是通过细胞外信号调节激酶/丝裂原活化蛋白（ERK/MAP）激酶依赖的机制实现的。当在miR-182-3p抑制剂存在的情况下抑制MYADM，或者在pre-miR-182-3p存在的情况下过表达MYADM时，人主动脉平滑肌细胞会恢复到分化表型。在体内，使用球囊损伤大鼠颈动脉模型，腺病毒-miR-182-3p通过降低MYADM表达显著抑制颈动脉新生内膜形成，而腺病毒-miR-182-3p抑制剂则显著促进新生内膜形成。血浆中不对称二甲基精氨酸水平高的患者的动脉粥样硬化病变显示miR-182-3p表达水平降低和MYADM表达水平升高。
miR-182-3p是一种通过靶向MYADM的新型SMC表型调节剂。
