Zuo Keqiang, Li Maoquan, Zhang Xiaoping, Lu Chenghui, Wang Shi, Zhi Kangkang, He Bin
Department of Interventional & Vascular Surgery, Shanghai Tenth People's Hospital, Tongji University School of Medicine Shanghai 200072, China.
Department of Vascular and Endovascular Surgery, Changzheng Hospital Shanghai 200003, China.
Int J Clin Exp Pathol. 2015 Jan 1;8(1):414-22. eCollection 2015.
Endothelial damage is strongly associated with cardiovascular diseases such as atherosclerosis. Bone marrow-derived endothelial progenitor cells (EPCs) play an important role in the maintenance of endothelial homeostasis and contribute to re-endothelialization of injured vessels as well as revascularization of ischemic tissues. MicroRNAs (miRNAs) have been reported to regulate EPC biological functions. In this study, we found that EPCs of atherosclerosis patients and EPCs exposed to hypoxia have increased expression of miRNA-21 (miR-21) as well as diminished ability to proliferate. MiR-21 knockdown rescued hypoxia-induced growth arrest in EPCs. Next, we used a luciferase reporter assay to demonstrate that miR-21 downregulates the expression of WW domain-containing protein 1 (WWP1), a negative regulator of TGFβ signaling, by directly targeting the 3'-UTR of WWP1. Finally, miR-21 overexpression or WWP1 knockdown in EPCs significantly activates the TGFβ signaling pathway and inhibits cell proliferation. Taken together, our results indicate that miR-21 suppresses EPC proliferation by activating the TGFβ signaling pathway via downregulation of WWP1. These findings may help the development of strategies to enhance the vitality of EPCs for therapeutic applications.
内皮损伤与动脉粥样硬化等心血管疾病密切相关。骨髓来源的内皮祖细胞（EPCs）在维持内皮稳态中发挥重要作用，并有助于损伤血管的再内皮化以及缺血组织的血管再生。据报道，微小RNA（miRNAs）可调节EPC的生物学功能。在本研究中，我们发现动脉粥样硬化患者的EPCs以及暴露于缺氧环境的EPCs中，微小RNA-21（miR-21）的表达增加，同时增殖能力减弱。敲低miR-21可挽救缺氧诱导的EPCs生长停滞。接下来，我们使用荧光素酶报告基因测定法证明，miR-21通过直接靶向WW结构域含蛋白1（WWP1）的3'-UTR来下调TGFβ信号的负调节因子WWP1的表达。最后，EPCs中miR-21的过表达或WWP1的敲低显著激活TGFβ信号通路并抑制细胞增殖。综上所述，我们的结果表明，miR-21通过下调WWP1激活TGFβ信号通路来抑制EPC增殖。这些发现可能有助于开发增强EPC活力以用于治疗应用的策略。
