钠-葡萄糖共转运蛋白 2 抑制剂达格列净可减轻糖尿病心肌病。

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.

背景：2 型糖尿病（DM2）是心力衰竭的危险因素，但目前尚无针对糖尿病性心脏病的特定治疗方法。钠-葡萄糖协同转运蛋白 2 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 心血管获益的临床数据突出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。然而，其保护的潜在机制尚不清楚。我们在 2 型糖尿病小鼠模型中研究了达格列净-SGLT2I 对糖尿病心肌病的影响。

方法：使用渗透型泵经皮下输注血管紧张素 II（ATII）30 天诱导糖尿病小鼠（db/db）发生心肌病。同时给予达格列净（1.5mg/kg/天）于饮水中。实验使用雄性同源、12-14 周龄 WT 或 db/db 小鼠（n=4-8/组）。体外将分离的心肌细胞暴露于葡萄糖（17.5-33mM）并给予达格列净处理。使用 indo-1 荧光指示剂测量细胞内钙瞬变。

结果：ATII 输注诱导 db/db 小鼠发生心肌病，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±57mg/dl，p<0.05）。此外，它还可减轻纤维化和炎症，并增加 ATII 处理的 db/db 小鼠的左心室缩短分数。在分离的心肌细胞中，达格列净降低了细胞内钙瞬变、炎症和 ROS 产生。最后，达格列净处理后电压依赖性 L 型钙通道（CACNA1C）、钠-钙交换体（NCX）和钠-氢交换体 1（NHE）膜转运体表达减少。

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相关的膜通道活性。通过减少纤维化、减轻炎症和改善收缩功能来体现其心脏保护作用。我们的研究结果提示了一种通过调节离子稳态来治疗糖尿病性心肌病的新型药物治疗方法。