LncRNA-SNHG5调控VDAC1信号通路在糖尿病心肌细胞铁死亡中的作用及机制研究

前期研究发现，VDAC1介导的线粒体功能障碍及心肌细胞铁死亡是糖尿病心肌病（DCM）的重要发病机制，但其上游调节机制不明确。预试验采用高糖处理心肌细胞，发现VDAC1升高伴随LncRNA SNHG5升高，同时VDAC1启动子区域组蛋白乙酰化水平升高、组蛋白去乙酰化酶2（HDAC2）水平降低；沉默SNHG5表达后，VDAC1水平降低，VDAC1启动子区域组蛋白乙酰化水平下降、HDAC2水平升高；但细胞总HDAC2 mRNA水平在各组间无明显差异，推测SNHG5通过影响HDAC2核内易位促进VDAC1组蛋白乙酰化，增加VDAC1表达，导致线粒体功能障碍及心肌细胞铁死亡。本课题拟在前期基础上，通过上调或抑制糖尿病大鼠和心肌细胞SNHG5表达，检测VDAC1及其组蛋白乙酰化水平、线粒体功能及铁死亡等指标变化，证实SNHG5/VDAC1信号通路在DCM中的作用及机制，为防治DCM提供新思路。

Cell death and mitochondrial dysfunction were involved in diabetic cardiomyopathy (DCM). Our preliminary experiments have found that voltage dependent anion channel protein 1 (VDAC1) can mediate mitochondrial dysfunction and induce ferroptosis. Long non-coding RNA plays an important role in diabetes and its complications. Our preliminary experiments showed that LncRNA SNHG5 was significantly increased in diabetic patients and cardiomyocytes treated with high glucose; and the expression of VDAC1 decreased after inhibiting SNHG5 expression. The occupation of H3K27 acetylation was significantly increased and HDAC2 was reduced on the promoter regions of VDAC1 in the cardiomyocytes treated with high glucose, and shRNA-SNHG5 dramatically reduced the occupation of H3K27ac and enrich the HDAC2 on the promoter regions of VDAC1. Therefore, we hypothesized that LncRNA SNHG5 might regulate the VDAC1 expression through HDAC2, and lead to ferroptosis. This project aims to further detect the changes of VDAC1, mitochondrial function and cell ferroptosis after upregulating or inhibiting of SNHG5 expression in diabetic rat and H9C2 cell. CHIP-qPCR, RIP-qPCR, RNA-FISH were used to determine whether SNHG5 regulates VDAC1 expression through HDAC2 to mediate the ferroptosis of cardiomyocytes. Our study is expected to clarify the role and molecular mechanism of SNHG5 in DCM, and provides new insights for the prevention and treatment of DCM.