MicroRNA-133a regulates insulin-like growth factor-1 receptor expression and vascular smooth muscle cell proliferation in murine atherosclerosis.
MicroRNA-133a regulates insulin-like growth factor-1 receptor expression and vascular smooth muscle cell proliferation in murine atherosclerosis.
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DOI：
10.1016/j.atherosclerosis.2013.11.029
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发表时间：
2014-01
期刊：
影响因子：
5.3
通讯作者：
Geng, Yong-Jian
中科院分区：
文献类型：
--
作者：
Gao, Song;Wassler, Michael;Zhang, Lulu;Li, Yangxin;Wang, Jun;Zhang, Yi;Shelat, Harnath;Williams, Jason;Geng, Yong-Jian
MicroRNA-133a （miR-133a）和胰岛素样生长因子-1 （IGF-1）是两种已知的调节心血管细胞增殖的不同分子。本研究在小鼠动脉粥样硬化模型中检测miR-133a是否影响IGF-1受体（IGF-1R）的表达和IGF-1刺激的血管平滑肌细胞（VSMC）的增殖。通过免疫荧光和免疫印迹分析野生型C57BL/6J （WT）和载脂蛋白e缺陷（ApoE−/−）小鼠主动脉中IGF-1R的表达，以及miR-133a的qRT-PCR表达。与WT主动脉相比，ApoE−/−主动脉中IGF-1R和miR-133a水平较低。在含有igf -1的培养基中，ApoE−/−VSMC的生长速度比WT细胞慢。miR-133a特异性抑制剂降低了miR-133a、IGF-1R的表达，igf -1刺激了脂蛋白缺乏培养基中的VSMC生长。相反，miR-133a前体增加IGF-1R水平，促进igf -1诱导的VSMC增殖。在荧光素酶- igf - 1r 3'UTR报告细胞系统中，miR-133a过表达的VSMC报告细胞荧光素酶活性未被抑制。IGF-1R mRNA在ApoE−/−VSMC中的半衰期短于WT VSMC。MiR-133a抑制剂减少了mRNA的半衰期，但前体增加了mRNA的半衰期，尽管在ApoE−/−VSMC中的作用不如在WT细胞中明显。MiR-133a通过延长IGF-1R mRNA的半衰期，作为IGF-1R表达的刺激因子。在ApoE缺乏诱导的动脉粥样硬化中，miR-133a表达降低与IGF-1R水平降低和VSMC生长抑制有关。给药miR-133a前体可能增强IGF-1刺激的VSMC存活和生长。
MicroRNA-133a (miR-133a) and insulin-like growth factor-1 (IGF-1) are two different molecules known to regulate cardiovascular cell proliferation. This study tested whether miR-133a affects expression of IGF-1 receptor (IGF-1R) and proliferation of IGF-1-stimulated vascular smooth muscle cells (VSMC) in a murine model of atherosclerosis. Expression of IGF-1R was analyzed by immuno-fluorescence and immuno-blotting, and miR-133a by qRT-PCR in the aortas of wild-type C57BL/6J (WT) and apolipoprotein-E deficient (ApoE−/−) mice. Compared to those in WT aortas, the IGF-1R and miR-133a levels were lower in ApoE−/− aortas. ApoE−/− VSMC grew slower than WT cells in the cultures with IGF-1-containing medium. MiR-133a-specific inhibitor decreased miR-133a, IGF-1R expression, IGF-1-stimulated VSMC growth in lipoprotein-deficient media. By contrast, miR-133a precursor increased IGF-1R levels and promoted IGF-1-induced VSMC proliferation. In the luciferase-IGF-1R 3’UTR reporter system, the reporter luciferase activity was not inhibited in VSMC with miR-133a overexpression. IGF-1R mRNA half-life in ApoE−/− VSMC was shorter than that in WT VSMC. MiR-133a inhibitor reduced but precursor increased the mRNA half-life, although the effects appeared less striking in ApoE−/− VSMC than in WT cells. MiR-133a serves as a stimulatory factor for IGF-1R expression through prolonging IGF-1R mRNA half-life. In atherosclerosis induced by ApoE deficiency, reduced miR-133a expression is associated with lower IGF-1R levels and suppressive VSMC growth. Administration of miR-133a precursor may potentiate IGF-1 stimulated VSMC survival and growth.
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