Department of Cardiology, First People's Hospital of Yunnan Province, Kunming, China.
Department of Cardiology, First People's Hospital of Yunnan Province, Kunming, China.
Metabolism. 2020 Jun;107:154226. doi: 10.1016/j.metabol.2020.154226. Epub 2020 Apr 8.
Aberrant endothelial function is a major contributing factor in cardiovascular disease. Dyslipidemia leads to decreased nitric oxide (NO) bioavailability, an early sign of endothelial failure. Low insulin gene enhancer protein (ISL1) levels decrease healthy NO bioavailability. We hypothesized that the microRNA miR-652-3p negatively regulates endothelial ISL1 expression and that dyslipidemia-induced miR-652-3p upregulation induces aberrant endothelial functioning via ISL1 downregulation.
Various in vitro experiments were conducted in human umbilical vein endothelial cells (HUVECs). Luciferase assays were performed in HEK293 cells. We constructed a high-fat diet (HFD) Apoe-/- murine model of dyslipidemia and a rat model of low-density lipoprotein (LDL)-induced dyslipidemia to conduct in vivo and ex vivo experiments.
Luciferase assays confirmed miR-652-3p's targeting of the ISL1 3'-untranslated region (3'-UTR). Simvastatin blocked oxidized LDL (ox-LDL)-induced increases in miR-652-3p and ox-LDL-induced decreases in ISL1 protein expression, endothelial NO synthase (eNOS) activation, and NO production. Simvastatin's effects were abrogated by miR-652-3p overexpression and phenocopied by miR-652-3p inhibition. The dyslipidemic mouse model exhibited increased miR-652-3p and decreased ISL1 protein levels in the endothelium, effects opposed by simvastatin or miR-652-3p inhibition. The impact of simvastatin in vivo was abolished by overexpressing miR-652-3p or knocking-down ISL1. The rat model of dyslipidemia exhibited a similar pattern of miR-652-3p upregulation, attenuated ISL1 protein levels, decreased eNOS activation, and decreased NO production, effects mitigated by simvastatin.
Dyslipidemia upregulates endothelial miR-652-3p, which decreases ISL1 protein levels, eNOS activation, and NO production. Simvastatin therapy lowers endothelial miR-652-3p expression to protect endothelial function under dyslipidemic conditions.
异常的内皮功能是心血管疾病的一个主要致病因素。血脂异常导致一氧化氮（NO）生物利用度降低，这是内皮功能衰竭的早期迹象。胰岛素基因增强子蛋白（ISL1）水平降低会降低健康的 NO 生物利用度。我们假设 microRNA miR-652-3p 负调控内皮细胞 ISL1 的表达，而血脂异常诱导的 miR-652-3p 上调通过下调 ISL1 引起异常的内皮功能。
在人脐静脉内皮细胞（HUVEC）中进行了各种体外实验。在 HEK293 细胞中进行了荧光素酶测定。我们构建了高脂饮食（HFD）Apoe-/- 血脂异常小鼠模型和低密度脂蛋白（LDL）诱导的血脂异常大鼠模型，以进行体内和体外实验。
荧光素酶测定证实了 miR-652-3p 靶向 ISL1 3'-非翻译区（3'-UTR）。辛伐他汀阻断了氧化型 LDL（ox-LDL）诱导的 miR-652-3p 增加和 ox-LDL 诱导的 ISL1 蛋白表达、内皮型一氧化氮合酶（eNOS）激活和 NO 产生减少。辛伐他汀的作用被 miR-652-3p 的过表达所阻断，被 miR-652-3p 的抑制所模拟。血脂异常小鼠模型的内皮细胞中 miR-652-3p 水平升高，ISL1 蛋白水平降低，辛伐他汀或 miR-652-3p 抑制则相反。在体内，辛伐他汀的作用被过表达 miR-652-3p 或敲低 ISL1 所阻断。血脂异常大鼠模型也表现出类似的 miR-652-3p 上调模式，ISL1 蛋白水平降低，eNOS 激活减少，NO 生成减少，辛伐他汀则减轻了这些影响。
血脂异常上调内皮细胞 miR-652-3p，降低 ISL1 蛋白水平、eNOS 激活和 NO 生成。辛伐他汀治疗降低内皮细胞 miR-652-3p 表达，在血脂异常情况下保护内皮功能。
