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

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。

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.