Rev-erbs agonist SR9009 alleviates ischemia-reperfusion injury by heightening endogenous cardioprotection at onset of type-2 diabetes in rats: Down-regulating ferritinophagy/ferroptosis signaling
Rev-erbs agonist SR9009 alleviates ischemia-reperfusion injury by heightening endogenous cardioprotection at onset of type-2 diabetes in rats: Down-regulating ferritinophagy/ferroptosis signaling
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DOI：
10.1016/j.biopha.2022.113595
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发表时间：
2022-08-24
影响因子：
7.5
通讯作者：
Xia，Zhong-Yuan
中科院分区：
文献类型：
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作者：
Huang，Qin;Tian，Liqun;Xia，Zhong-Yuan
2型糖尿病(T2 DM)的复杂进展导致对心肌缺血再灌注(IR)易感性的研究结果不一致。多个器官的IR损伤与铁性下垂相关。靶向REV-ERBS可能会限制铁性下垂，越来越多的注意力转向昼夜节律药物的应用来治疗IR损伤。然而，REV-ERBS激动剂SR9009是否能减轻糖尿病IR损伤仍不清楚。在这里，我们研究了大鼠在T2 DM发病时对IR的易感性，以及SR9009和铁蛋白吞噬/铁下垂信号之间的潜在关联。采用高脂饮食加小剂量链脲佐菌素腹腔注射建立T2 DM动物模型。同时建立心肌缺血再灌注模型。观察和分析大鼠一般特征、心功能、糖脂变化、血清生化、细胞凋亡指数(AI)和形态组织学变化。Western印迹和免疫荧光(IF)法检测噬铁蛋白/铁下垂信号的表达及其共定位。糖尿病大鼠的糖脂分布和心脏舒张期功能明显受损。与非糖尿病大鼠相比，糖尿病大鼠心肌组织中CK-MB、AI水平及吞铁/铁下垂相关蛋白表达水平降低。铁下垂诱导剂Erastin上调糖尿病大鼠血清中的超氧化物歧化酶、丙二醛和AI水平，以及吞铁/铁下垂相关蛋白的表达，使其向IR方向发展。与使用或不使用Erastin治疗的糖尿病大鼠相比，SR9009治疗下调了糖尿病大鼠的心肌损伤程度和吞铁/铁下垂相关蛋白的表达。T2 DM的发病激活了对心肌IR损伤易感性的内源性心脏保护，而SR9009通过下调吞铁蛋白/铁下垂信号，外源性增强了这一内源性机制，减轻了T2 DM发病时的心肌IR损伤。
The complex progression of type-2 diabetes (T2DM) results in inconsistent findings on myocardial susceptibility to ischemia-reperfusion (IR). IR injuries in multiple organs interconnect with ferroptosis. Targeting Rev-erbs might limit ferroptosis, with increasing attention turning to the application of circadian medicine against IR injuries. However, whether the Rev-erbs agonist SR9009 could mitigate diabetic IR injury remains unknown. Here, we investigated the susceptibility to IR at onset of T2DM in rats and its potential association between SR9009 and ferritinophagy/ferroptosis signaling. Onset of T2DM model was induced with a high-fat diet and the intraperitoneal injection of a low dose of streptozotocin. Myocardial IR model was established as well. Rats’ general characteristics, cardiac function, glycolipid profiles, serum biochemistry, apoptosis index (AI) and morphological histology were observed and analyzed. Western blot and immunofluorescence (IF) were employed to evaluate the expression of ferritinophagy/ferroptosis signaling and its co-localization. Glycolipid profiles and cardiac diastolic function were significantly impaired in diabetic rats. CK-MB, AI levels and ferritinophagy/ferroptosis-related proteins expression decreased towards myocardial IR in diabetic rats compared to non-diabetic rats’. The ferroptosis inducer Erastin up-regulated SOD, MDA, and AI levels, as well as the expression of ferritinophagy/ferroptosis-related proteins in diabetic rats towards IR. Treatment with SR9009 down-regulated the degree of myocardial injury and ferritinophagy/ferroptosis-related proteins expression compared to diabetic rats treated with or without Erastin. Onset of T2DM activated endogenous cardioprotection against the susceptibility to myocardial IR injury, and SR9009 exogenously enhanced this endogenous mechanism and alleviated myocardial IR injury at onset of T2DM by down-regulating ferritinophagy/ferroptosis signaling.