Cardiovascular Division, Department of Internal Medicine, Abboud Cardiovascular Research Center, University of Iowa Carver College of Medicine, Iowa City, USA.
University of California, San Diego, USA.
Sci Rep. 2017 Feb 9;7:42265. doi: 10.1038/srep42265.
Sirtuin1 (Sirt1) is a class III histone deacetylase that regulates a variety of physiological processes, including endothelial function. Caveolin1 (Cav1) is also an important determinant of endothelial function. We asked if Sirt1 governs endothelial Cav1 and endothelial function by regulating miR-204 expression and endoplasmic reticulum (ER) stress. Knockdown of Sirt1 in endothelial cells, and in vivo deletion of endothelial Sirt1, induced endothelial ER stress and miR-204 expression, reduced Cav1, and impaired endothelium-dependent vasorelaxation. All of these effects were reversed by a miR-204 inhibitor (miR-204 I) or with overexpression of Cav1. A miR-204 mimic (miR-204 M) decreased Cav1 in endothelial cells. In addition, high-fat diet (HFD) feeding induced vascular miR-204 and reduced endothelial Cav1. MiR-204-I protected against HFD-induced downregulation of endothelial Cav1. Moreover, pharmacologic induction of ER stress with tunicamycin downregulated endothelial Cav1 and impaired endothelium-dependent vasorelaxation that was rescued by overexpressing Cav1. In conclusion, Sirt1 preserves Cav1-dependent endothelial function by mitigating miR-204-mediated vascular ER stress.
Sirtuin1（Sirt1）是一种 III 类组蛋白去乙酰化酶，可调节多种生理过程，包括内皮功能。窖蛋白 1（Cav1）也是内皮功能的重要决定因素。我们询问 Sirt1 是否通过调节 miR-204 表达和内质网（ER）应激来控制内皮细胞 Cav1 和内皮功能。内皮细胞中 Sirt1 的敲低和内皮细胞中 Sirt1 的缺失诱导内皮细胞 ER 应激和 miR-204 表达，降低 Cav1，并损害内皮依赖性血管舒张。所有这些作用都可以通过 miR-204 抑制剂（miR-204 I）或 Cav1 的过表达来逆转。miR-204 模拟物（miR-204 M）降低了内皮细胞中的 Cav1。此外，高脂肪饮食（HFD）喂养诱导血管 miR-204 并降低内皮细胞 Cav1。miR-204-I 可预防 HFD 诱导的内皮细胞 Cav1 下调。此外，用衣霉素诱导 ER 应激会下调内皮细胞 Cav1，并损害内皮依赖性血管舒张，而过表达 Cav1 可挽救这一作用。总之，Sirt1 通过减轻 miR-204 介导的血管内质网应激来维持 Cav1 依赖性内皮功能。
