Departments of Cardiovascular, Renal and Metabolic Medicine (H.O., Ta.M., A.K., M.M., T.S., M.T., T.Y., K.N., Y.K., K.A., W.O., Te.M.), Pharmacology (A.K.), and Cellular Physiology and Signal Transduction (T.S.), Sapporo Medical University School of Medicine, Sapporo, Japan.
Departments of Cardiovascular, Renal and Metabolic Medicine (H.O., Ta.M., A.K., M.M., T.S., M.T., T.Y., K.N., Y.K., K.A., W.O., Te.M.), Pharmacology (A.K.), and Cellular Physiology and Signal Transduction (T.S.), Sapporo Medical University School of Medicine, Sapporo, Japan
J Pharmacol Exp Ther. 2019 Mar;368(3):524-534. doi: 10.1124/jpet.118.253666. Epub 2018 Dec 14.
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 -hydroxybutyrate (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 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.
SGLT2 抑制剂降低糖尿病患者心脏事件的机制尚不清楚。在这里，我们研究了 SGLT2 抑制剂在 2 型糖尿病（DM）动物模型中对心肌梗死（MI）后急性存活率的影响，以及对心脏代谢组和抗氧化蛋白的可能修饰作用。在 DM Otsuka Long-Evans Tokushima Fatty（OLETF）大鼠和 Long-Evans Tokushima Otsuka（LETO）对照大鼠中诱导 MI。在 MI 前用恩格列净（每天 10mg/kg，14 天）治疗可降低 OLETF 大鼠的血糖并增加血液和心肌 -羟基丁酸（OHB）水平。MI 后 48 小时 OLETF 大鼠的存活率明显低于 LETO 大鼠（40%比 84%），恩格列净可将 OLETF 大鼠的存活率显著提高至 70%，尽管 MI 大小相当。OLETF 大鼠非梗塞心肌中的代谢组和基因表达模式与增加的脂肪酸氧化和减少的葡萄糖氧化一致。恩格列净改变了这些模式，表明 OLETF 大鼠的葡萄糖氧化和酮体利用均增加。恩格列净可防止 MI 后非梗塞心肌中 ATP 水平降低，并显著增加 OLETF 大鼠心肌中 Sirt3 和超氧化物歧化酶 2 的水平。OHB 的给药部分模拟了恩格列净在 OLETF 大鼠中的作用。结果表明，恩格列净可预防 DM 诱导的 MI 后死亡率增加，可能通过对心脏能量代谢和抗氧化蛋白的保护性修饰。
