HUR通过PIM1调控线粒体分裂参与高血压血管内皮细胞损伤的机制研究

Mitochondrial dysfunction plays a pivotal role in the pathogenesis of hypertension-related vascular endothelial cell injury. Our prior study has demonstrated that mitochondrial fission mediated mitochondrial dysfunction induced by angiotensin Ⅱ (AngⅡ). But, the exact regulation mechanisms remain to be elucidated. The PIM proteins are a family of highly homologous serine/threonine kinases. PIM1, a member of the PIM kinase family, mediates mitochondrial fission by regulating Drp1. In addition, HuR can regulate PIM1 expression by enhancing its mRNA stability. Our preliminary studies demonstrated that : (1) the expression of HUR and PIM1 are decreased in endothelial cells induced by AngⅡ. (2) The overexpression of HUR can up-regulate PIM1 expression by stabilizing PIM1 mRNA, reduce mitochondrial fission and eventually inhibit endothelial cell injury. Hence, we hypothesize here that HUR-PIM1-Drp1 signaling pathway may participate in the process of AngⅡ-induced endothelial cell injury by targeting mitochondrial fission in hypertension. To clarify our hypothesis, proposed investigations are designed to uncover the effects of HUR-PIM1-Drp1 signaling pathway and mitochondrial fission in hypertension-related endothelial cell injury both in cultured human umbilical vein endothelial cells and in animal experiments. We hope to reveal the molecular mechanism of mitochondrial fission in hypertension-related endothelial cell injury. Our project will provide a new idea for prevention and cure of hypertension and hypertension-related cardiovascular diseases.

线粒体功能损伤在高血压血管内皮细胞损伤中作用重要。我们前期研究发现线粒体分裂介导血管紧张素Ⅱ（AngⅡ）引起的线粒体功能损伤，但具体机制尚未完全阐明。丝氨酸/苏氨酸蛋白激酶家族成员PIM1调控Drp1是线粒体分裂的重要机制，PIM1 mRNA稳定性受RNA结合蛋白人抗原R（HUR）调控。我们预实验发现：①AngⅡ抑制内皮细胞HUR及PIM1表达；②过表达HUR可稳定PIM1 mRNA并上调PIM1表达，减少线粒体分裂，最终抑制内皮细胞损伤。因此我们推测：高血压过程中，AngⅡ通过抑制HUR表达使PIM1 mRNA稳定性减弱、PIM1表达减少，引起线粒体分裂增加，最终导致线粒体功能损伤及内皮细胞损伤。本课题拟通过体外培养人脐静脉内皮细胞、血管内皮细胞特异性HUR和PIM1转基因小鼠阐明HUR通过PIM1调控线粒体分裂在高血压血管内皮细胞损伤中的作用，为高血压相关心血管疾病防治提供新的思路。

高血压是心血管病最主要的危险因素和原因，是当今社会威胁人类健康的最重要疾病之一。血管内皮损伤是高血压相关心血管疾病发生发展的关键环节，线粒体功能损伤介导的活性氧异常增多在内皮细胞损伤中扮演着重要角色。但在高血压疾病中调控线粒体损伤的机制尚未完全阐明。我们在前期研究基础上，从细胞及动物层面进一步探究线粒体分裂在高血压发病中的作用及调控机制。结果提示：在 AngⅡ等损伤刺激下，血管内皮细胞 HUR表达降低使 PIM1 mRNA稳定性减弱并抑制 PIM1表达，PIM1表达减少使其磷酸化 Drp1（Ser637位点）能力减弱，Drp1活性增强，诱导线粒体分裂，进而诱发线粒体功能损伤，最终导致内皮细胞损伤的发生。研究结果有助于阐明线粒体损伤的机制，为高血压相关心血管疾病的防治提供理论依据。