Empagliflozin 通过能量调节在小鼠心力衰竭模型中改善心脏线粒体功能和存活率

Empagliflozin improves cardiac mitochondrial function and survival

through energy regulation in a murine model of heart failure. 

Keywords：Empagliflozin; Energy metabolism; Heart failure; Mitochondria; SGLT2 inhibitor

关键词：恩格列净；能量代谢；心脏衰竭; 线粒体; SGLT2抑制剂

哺乳动物：小鼠

组织：心脏
作者：Shiraki Aya, Oyama Jun-Ichi, Shimizu Takahiko, Nakajima Takayuki, Yokota Takashi, Node Koichi

出版期刊：《Eur J Pharmacol》（2022）

Abstract：

Sodium-glucose cotransporter 2 (SGLT2) inhibitors have been demonstrated to have beneficial effects on HF in large clinical trials; however, the mechanisms remain to be elucidated. The aim of this study was to clarify the mechanisms by which empagliflozin, one of SGLT2 inhibitors, affects heart failure. Method and results: Eight-week-old male mice deficient for heart and skeletal muscle-specific manganese superoxide dismutase (MnSOD-cKO mice), a murine model of dilated cardiomyopathy, were given food mixed with or without 10 mg/kg empagliflozin for 7 weeks and evaluated. Both the survival rate and cardiac fibrosis were significantly improved in the empagliflozin group. The capacity for oxidative phosphorylation in cardiac mitochondria was significantly upregulated as measured with Oxygraph-2k respirometer, and blood lactate levels produced by anaerobic metabolism were significantly lower in the empagliflozin group. Energy expenditure was significantly improved in the empagliflozin group, measured by respiratory gas analysis, with a concomitant reduction in serum leptin concentration and increase in food intake. A moderate amount of glucose was excreted in urine in the empagliflozin group; however, the available energy substrate in the body nonetheless expanded because of the much higher caloric intake. Conclusions: We conclude that empagliflozin improved cardiac mitochondrial function and upregulated energy metabolism even in HF in mice. These findings provide novel mechanisms for the beneficial effects of SGLT2 inhibitors on HF. 

文章摘要：

在大型临床试验中，钠-葡萄糖协同转运蛋白 2 (SGLT2) 抑制剂已被证明对 HF 有益。然而，这些机制仍有待阐明。本研究的目的是阐明 SGLT2 抑制剂之一 empagliflozin 影响心力衰竭的机制。方法和结果：心脏和骨骼肌特异性锰超氧化物歧化酶缺乏的 8 周龄雄性小鼠（MnSOD-cKO 小鼠），一种扩张型心肌病的小鼠模型，在 7 天的时间内给予与 10 mg/kg 恩格列净混合的食物。周和评估。恩格列净组的存活率和心脏纤维化均显着改善。用 Oxygraph-2k 呼吸计测量，心脏线粒体中氧化磷酸化的能力显着上调，并且在 empagliflozin 组中，无氧代谢产生的血乳酸水平显着降低。通过呼吸气体分析测量，恩格列净组的能量消耗显着改善，同时血清瘦素浓度降低，食物摄入增加。恩格列净组尿中排出适量葡萄糖；然而，由于卡路里摄入量高得多，体内可用的能量基质仍然增加了。结论：我们得出结论，即使在小鼠 HF 中，empagliflozin 也能改善心脏线粒体功能并上调能量代谢。这些发现为 SGLT2 抑制剂对 HF 的有益作用提供了新的机制。

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