Empagliflozin, an SGLT2 Inhibitor, Reduced the Mortality Rate after Acute Myocardial Infarction with Modification of Cardiac Metabolomes and Antioxidants in Diabetic Rats
Empagliflozin, an SGLT2 Inhibitor, Reduced the Mortality Rate after Acute Myocardial Infarction with Modification of Cardiac Metabolomes and Antioxidants in Diabetic Rats
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DOI：
10.1124/jpet.118.253666
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发表时间：
2019-03-01
影响因子：
3.5
通讯作者：
Miura, Tetsuji
中科院分区：
文献类型：
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作者：
Oshima, Hiroto;Miki, Takayuki;Miura, Tetsuji
SGLT 2抑制剂减少糖尿病患者心脏事件的机制尚不清楚。在此，我们研究了SGLT 2抑制剂对2型糖尿病（DM）动物模型心肌梗死（MI）后急性存活率的影响，以及心脏代谢组和抗氧化蛋白修饰的可能参与。在DM Otsuka Long-Evans德岛Fatty（OLETF）大鼠和Long-Evans德岛Otsuka（LETO）对照大鼠中诱导MI。MI前恩格列净治疗（10 mg/kg/天，14天）降低了OLETF的血糖，并增加了血液和心肌β-羟基丁酸（β OHB）水平。OLETF大鼠MI后48小时的存活率显著低于LETO大鼠（40% vs. 84%），恩格列净显著改善了OLETF大鼠的存活率至70%，尽管MI大小相当。OLETF大鼠非梗死心肌的代谢组和基因表达模式与脂肪酸氧化增加和葡萄糖氧化减少一致。恩格列净改变了这些模式，表明OLETF大鼠的葡萄糖氧化和酮利用增加。恩格列净可防止MI后非梗死心肌ATP水平下降，并显着增加OLETF大鼠心肌Sirt 3和超氧化物歧化酶2的水平。β OHB给药部分模拟了恩格列净在OLETF大鼠中的作用。结果表明，恩格列净可能通过保护性改变心脏能量代谢和抗氧化蛋白，预防DM诱导的MI后死亡率增加。
The mechanism by which SGLT2 inhibitors reduce cardiac events in diabetic patients remains unclear. Here, we examined the effects of an SGLT2 inhibitor on the acute survival rate after myocardial infarction (MI) in an animal model of type 2 diabetes mellitus (DM) and the possible involvement of modification of cardiac metabolomes and antioxidative proteins. MI was induced in DM Otsuka Long-Evans Tokushima Fatty (OLETF) rats and Long-Evans Tokushima Otsuka (LETO) control rats. Treatment with empagliflozin (10 mg/kg per day, 14 days) before MI reduced blood glucose and increased blood and myocardial beta-hydroxybutyrate (beta OHB) levels in OLETF. Survival rate at 48 hours after MI was significantly lower in OLETF rats than in LETO rats (40% vs. 84%), and empagliflozin significantly improved the survival rate in OLETF rats to 70%, although the sizes of MI were comparable. Patterns of metabolomes and gene expression in the noninfarcted myocardium of OLETF rats were consistent with increased fatty acid oxidation and decreased glucose oxidation. The patterns were modified by empagliflozin, suggesting both increased glucose oxidation and ketone utilization in OLETF rats. Empagliflozin prevented reduction of ATP level in the noninfarcted myocardium after MI and significantly increased myocardial levels of Sirt3 and superoxide dismutase 2 in OLETF rats. Administration of beta OHB partially mimicked the effects of empagliflozin in OLETF rats. The results suggest that empagliflozin prevents DM-induced increase in post-MI mortality, possibly by protective modification of cardiac energy metabolism and antioxidant proteins.