BACKGROUND Diabetes mellitus type 2 (DM2) is a risk factor for developing heart failure but there is no specific therapy for diabetic heart disease. Sodium glucose transporter 2 inhibitors (SGLT2I) are recently developed diabetic drugs that primarily work on the kidney. Clinical data describing the cardiovascular benefits of SGLT2Is highlight the potential therapeutic benefit of these drugs in the prevention of cardiovascular events and heart failure. However, the underlying mechanism of protection remains unclear. We investigated the effect of Dapagliflozin-SGLT2I, on diabetic cardiomyopathy in a mouse model of DM2. METHODS Cardiomyopathy was induced in diabetic mice (db/db) by subcutaneous infusion of angiotensin II (ATII) for 30 days using an osmotic pump. Dapagliflozin (1.5 mg/kg/day) was administered concomitantly in drinking water. Male homozygous, 12-14 weeks old WT or db/db mice (n = 4-8/group), were used for the experiments. Isolated cardiomyocytes were exposed to glucose (17.5-33 mM) and treated with Dapagliflozin in vitro. Intracellular calcium transients were measured using a fluorescent indicator indo-1. RESULTS Angiotensin II infusion induced cardiomyopathy in db/db mice, manifested by cardiac hypertrophy, myocardial fibrosis and inflammation (TNFα, TLR4). Dapagliflozin decreased blood glucose (874 ± 111 to 556 ± 57 mg/dl, p < 0.05). In addition it attenuated fibrosis and inflammation and increased the left ventricular fractional shortening in ATII treated db/db mice. In isolated cardiomyocytes Dapagliflozin decreased intracellular calcium transients, inflammation and ROS production. Finally, voltage-dependent L-type calcium channel (CACNA1C), the sodium-calcium exchanger (NCX) and the sodium-hydrogen exchanger 1 (NHE) membrane transporters expression was reduced following Dapagliflozin treatment. CONCLUSION Dapagliflozin was cardioprotective in ATII-stressed diabetic mice. It reduced oxygen radicals, as well the activity of membrane channels related to calcium transport. The cardioprotective effect manifested by decreased fibrosis, reduced inflammation and improved systolic function. The clinical implication of our results suggest a novel pharmacologic approach for the treatment of diabetic cardiomyopathy through modulation of ion homeostasis.

中文翻译：

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葡萄糖-葡萄糖共转运蛋白2抑制剂Dapagliflozin可减轻糖尿病性心肌病。

背景技术2型糖尿病（DM2）是发生心力衰竭的危险因素，但是没有针对糖尿病性心脏病的特异性疗法。葡萄糖转运蛋白2钠抑制剂（SGLT2I）是最近开发的糖尿病药物，主要作用于肾脏。描述SGLT2I的心血管益处的临床数据凸显了这些药物在预防心血管事件和心力衰竭方面的潜在治疗益处。但是，保护的基本机制仍不清楚。我们调查了DM2小鼠模型中Dapagliflozin-SGLT2I对糖尿病性心肌病的影响。方法采用渗透泵皮下注射血管紧张素II（ATII）30天，在糖尿病小鼠（db / db）中诱发心肌病。达格列净（1.5 mg / kg /天）在饮用水中同时给药。将12-14周龄的雄性纯合WT或db / db小鼠（n ＝ 4-8 /组）用于实验。将分离的心肌细胞暴露于葡萄糖（17.5-33 mM），并在体外用达格列净治疗。使用荧光指示剂indo-1测量细胞内钙瞬变。结果血管紧张素II输注引起的db / db小鼠心肌病，表现为心脏肥大，心肌纤维化和炎症（TNFα，TLR4）。达格列净降低血糖（874±111至556±57 mg / dl，p <0.05）。此外，它减轻了ATII处理的db / db小鼠的纤维化和炎症，并增加了左心室缩短。在分离的心肌细胞中，达格列净降低细胞内钙瞬变，炎症和ROS产生。最后，电压依赖性L型钙通道（CACNA1C）Dapagliflozin处理后，钠钙交换剂（NCX）和钠氢交换剂1（NHE）膜转运蛋白的表达降低。结论达格列净对ATII应激的糖尿病小鼠具有心脏保护作用。它减少了氧自由基，以及与钙转运有关的膜通道的活性。通过减少纤维化，减少炎症和改善收缩功能来表现出心脏保护作用。我们结果的临床意义表明，通过调节离子稳态来治疗糖尿病性心肌病的新药理方法。以及与钙转运有关的膜通道活性。通过减少纤维化，减少炎症和改善收缩功能来表现出心脏保护作用。我们结果的临床意义表明，通过调节离子稳态来治疗糖尿病性心肌病的新药理方法。以及与钙转运有关的膜通道活性。通过减少纤维化，减少炎症和改善收缩功能来表现出心脏保护作用。我们结果的临床意义表明，通过调节离子稳态来治疗糖尿病性心肌病的新药理方法。