Upregulation of let-7a inhibits vascular smooth muscle cell proliferation in vitro and in vein graft intimal hyperplasia in rats

作者：Cao, Hui; Hu, Xinhua^*; Zhang, Qiang; Wang, Junpeng; Li, Jun; Liu, Bing; Shao, Yang; Li, Xi; Zhang, Jian; Xin, Shijie

来源：Journal of Surgical Research, 2014, 192(1): 223-233.

DOI：10.1016/j.jss.2014.05.045

• Let-7a
• Vascular smooth muscle cells
• Vein graft
• Intimal hyperplasia
• Proliferation

Background: Proliferation of vascular smooth muscle cells ( VSMCs) is a crucial event in the pathogenesis of intimal hyperplasia, which is the main cause of restenosis after vascular reconstruction. In this study, we assessed the impact of let-7a microRNA ( miRNA) on the proliferation of VSMCs.
Methods: Using miRNA microarrays analysis for miRNA expression in the vein graft model. Lentiviral vector-mediated let-7a was transfected into the vein grafts. In situ hybridization was performed to detect let-7a. Cultured rat VSMCs were transfected with let-7a mimics for different periods of time. Cell proliferation, migration and cell cycle activity were monitored following transfection of the let-7a mimics. Immunohistochemical and Western blotting analysis the expression levels of c-myc and K-ras.
Results: We found that let-7a was the most downregulated miRNA in the vein graft model. In vivo proliferation of VSMCs was assessed in a rat model of venous graft intimal hyperplasia. Let-7a was found to localize mainly to the VSMCs. Let-7a miRNA expression was increased in VSMCs in the neointima of the let-7a treated group. Intimal hyperplasia was suppressed by upregulation of let-7a via lentiviral vector-mediated mimics. In cultured VSMCs, the expression of let-7a increased upon starving, and the upregulation of let-7a miRNA significantly decreased cell proliferation and migration. Immunohistochemical and Western blotting analysis demonstrated that treatment with let-7a mimics resulted in decreased expression levels of c-myc and K-ras.
Conclusions: The results indicate that let-7a miRNA is a novel regulator of VSMC proliferation in intimal hyperplasia. These findings suggest that let-7a miRNA is a promising therapeutic target for the prevention of intimal hyperplasia.

• 出版日期2014-11
• 单位中国医科大学