Inhibition of Aberrant MicroRNA-133a Expression in Endothelial Cells by Statin Prevents Endothelial Dysfunction by Targeting GTP Cyclohydrolase 1 in Vivo.
Inhibition of Aberrant MicroRNA-133a Expression in Endothelial Cells by Statin Prevents Endothelial Dysfunction by Targeting GTP Cyclohydrolase 1 in Vivo.
复制标题
他汀类药物抑制内皮细胞中异常的 MicroRNA-133a 表达，通过体内靶向 GTP 环化水解酶 1 预防内皮功能障碍。
DOI：
10.1161/circulationaha.116.017949
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发表时间：
2016-11-29
期刊：
影响因子：
37.8
通讯作者：
Wang SX
中科院分区：
文献类型：
--
作者：
Li P;Yin YL;Guo T;Sun XY;Ma H;Zhu ML;Zhao FR;Xu P;Chen Y;Wan GR;Jiang F;Peng QS;Liu C;Liu LY;Wang SX
背景：GTP环化水解酶1（GCH 1）缺乏是内皮功能障碍中内皮型一氧化氮合酶解偶联的关键。microRNA（miRs）是一类负调控基因表达的调控RNA。我们研究了他汀类药物是否通过miR依赖性GCH 1上调来预防内皮功能障碍。方法：通过测定器官腔中乙酰胆碱诱导的血管舒张来评估内皮功能。通过定量逆转录聚合酶链反应和荧光原位杂交评估miR-133 a表达。结果：我们首次证明了GCH 1 mRNA是miR-133 a的靶基因。在内皮细胞中，miR-133 a被细胞因子/氧化剂强烈诱导，并被洛伐他汀抑制。此外，洛伐他汀上调GCH 1和四氢生物蝶呤，并在应激内皮细胞中重新偶联内皮型一氧化氮合酶。洛伐他汀的这些作用被强制的miR-133 a表达所消除，并被miR-133 a抑制剂所反映。在小鼠中，高脂血症或高血糖症诱导血管内皮中的异位miR-133 a表达，降低GCH 1蛋白和四氢生物蝶呤水平，并损害内皮功能，这些都被洛伐他汀或miR-133 a阿托伐他汀逆转。洛伐他汀在小鼠中的这些有益作用通过体内miR-133 a过表达或GCH 1敲低而消除。在大鼠中，包括高血糖症、血脂异常和高同型半胱氨酸血症在内的多种心血管危险因素导致miR-133 a血管表达增加、GCH 1表达减少、内皮一氧化氮合酶功能解偶联并诱导内皮功能障碍，而这些都可以通过洛伐他汀来预防。结论：他汀类药物可通过靶向GCH 1抑制血管内皮细胞中miR-133 a的异常表达，从而预防血管内皮功能障碍。因此，miR-133 a代表了预防心血管疾病的重要治疗靶点。
Background: GTP cyclohydrolase 1 (GCH1) deficiency is critical for endothelial nitric oxide synthase uncoupling in endothelial dysfunction. MicroRNAs (miRs) are a class of regulatory RNAs that negatively regulate gene expression. We investigated whether statins prevent endothelial dysfunction via miR-dependent GCH1 upregulation. Methods: Endothelial function was assessed by measuring acetylcholine-induced vasorelaxation in the organ chamber. MiR-133a expression was assessed by quantitative reverse transcription polymerase chain reaction and fluorescence in situ hybridization. Results: We first demonstrated that GCH1 mRNA is a target of miR-133a. In endothelial cells, miR-133a was robustly induced by cytokines/oxidants and inhibited by lovastatin. Furthermore, lovastatin upregulated GCH1 and tetrahydrobiopterin, and recoupled endothelial nitric oxide synthase in stressed endothelial cells. These actions of lovastatin were abolished by enforced miR-133a expression and were mirrored by a miR-133a antagomir. In mice, hyperlipidemia- or hyperglycemia-induced ectopic miR-133a expression in the vascular endothelium, reduced GCH1 protein and tetrahydrobiopterin levels, and impaired endothelial function, which were reversed by lovastatin or miR-133a antagomir. These beneficial effects of lovastatin in mice were abrogated by in vivo miR-133a overexpression or GCH1 knockdown. In rats, multiple cardiovascular risk factors including hyperglycemia, dyslipidemia, and hyperhomocysteinemia resulted in increased miR-133a vascular expression, reduced GCH1 expression, uncoupled endothelial nitric oxide synthase function, and induced endothelial dysfunction, which were prevented by lovastatin. Conclusions: Statin inhibits aberrant miR-133a expression in the vascular endothelium to prevent endothelial dysfunction by targeting GCH1. Therefore, miR-133a represents an important therapeutic target for preventing cardiovascular diseases.