The microRNA miR-132 targets Lrrfip1 to block vascular smooth muscle cell proliferation and neointimal hyperplasia
The microRNA miR-132 targets Lrrfip1 to block vascular smooth muscle cell proliferation and neointimal hyperplasia
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DOI：
10.1016/j.atherosclerosis.2013.05.009
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发表时间：
2013-08-01
期刊：
影响因子：
5.3
通讯作者：
Kook, Hyun
中科院分区：
文献类型：
--
作者：
Choe, Nakwon;Kwon, Jin-Sook;Kook, Hyun
目的：血管平滑肌细胞（VSMCs）的增殖和重塑是动脉粥样硬化和再狭窄的重要病理过程。方法和结果：microRNA微阵列显示，导管损伤后大鼠颈动脉中miR-132表达上调，并通过实时荧光定量RT-PCR进一步证实。转染miR-132模拟物可显著抑制VSMC增殖，而转染miR-132模拟物则可增加VSMC增殖，miR-132模拟物可抑制VSMC迁移并诱导凋亡。miR-132模拟物增加了p27和平滑肌（SM）α-肌动蛋白的蛋白量，而它减少了SM α-肌动蛋白和Bcl 2。生物信息学研究表明，LRRFIP 1是miR-132的候选靶点。miR-132以序列特异性方式下调由含有Lrrfip 1的30-非翻译区的载体驱动的荧光素酶活性。LRFIP 1诱导VSMC增殖并增加ERK的磷酸化。免疫组化结果显示，LrRFIP 1沿着平滑肌基底层区域表达，在动脉损伤后7 d表达模式被破坏。LRFIP 1 mRNA在伤后14天下降。miR-132在大鼠颈动脉中的表达降低，并减弱了颈动脉损伤模型中的新生内膜增殖。结论：我们的研究结果表明，miR-132是一种新的调节VSMC增殖，抑制新生内膜形成抑制LRRFIP 1的表达。(C)2013爱思唯尔爱尔兰有限公司版权所有。
Objective: The proliferation and remodeling of vascular smooth muscle cells (VSMCs) is an important pathological event in atherosclerosis and restenosis. Here we report that microRNA-132 (miR-132) blocks vascular smooth muscle cells (VSMC) proliferation by inhibiting the expression of LRRFIP1 [leucine-rich repeat (in Flightless 1) interacting protein-1].Methods and results: MicroRNA microarray revealed that miR-132 was upregulated in the rat carotid artery after catheter injury, which was further confirmed by quantitative real-time RT-PCR. Transfection of a miR-132 mimic significantly inhibited the proliferation of VSMCs, whereas transfection of a miR-132 antagomir increased it. miR-132 mimic inhibited VSMC migration and induced apoptosis. miR-132 mimic increased the protein amounts of both p27 and smooth muscle (SM) alpha-actin, whereas it decreased SM alpha-actin and Bcl2. Bioinformatics showed that LRRFIP1 is a target candidate of miR-132. miR-132 downregulated luciferase activity driven by a vector containing the 30-untranslated region of Lrrfip1 in a sequence-specific manner. LRRFIP1 induced VSMC proliferation and increased phosphorylation of ERK. Immunohistochemical analysis revealed that Lrrfip1 was clearly expressed along with the basal laminar area of smooth muscle, and its expression pattern was disrupted 7 days after arterial injury. LRRFIP1 mRNA was decreased 14 days after injury. Delivery of miR-132 to rat carotid artery reduced LRRFIP1 expression and attenuated neointimal proliferation in carotid artery injury models.Conclusions: Our results suggest that miR-132 is a novel regulator of VSMC proliferation that represses neointimal formation by inhibiting LRRFIP1 expression. (C) 2013 Elsevier Ireland Ltd. All rights reserved.