Department of Cardiology, Renmin Hospital of Wuhan University, 238 Jiefang Road, Wuhan, Hubei, 430060, China; Cardiovascular Research Institute of Wuhan University, Wuhan, China; Hubei Key Laboratory of Cardiology, Wuhan, China.
Department of Cardiology, Renmin Hospital of Wuhan University, 238 Jiefang Road, Wuhan, Hubei, 430060, China; Cardiovascular Research Institute of Wuhan University, Wuhan, China; Hubei Key Laboratory of Cardiology, Wuhan, China.
Eur J Pharmacol. 2022 Dec 5;936:175357. doi: 10.1016/j.ejphar.2022.175357. Epub 2022 Oct 28.
Ventricular arrhythmias (VAs) after myocardial infarction (MI) are an important cause of death in patients. Inhibition of sodium-glucose ligand transporter type 2 (SGLT-2) has been shown to reduce cardiovascular mortality in myocardial infarction independent of glycemic sham and prevent ventricular arrhythmias, and it is unclear whether these effects can be further enhanced by additional SGLT-1 inhibition. We investigated the effects of chronic treatment with the dual SGLT-1 and 2 inhibitor sotagliflozin (Sto) on VAs and their underlying mechanisms after MI.
MI was induced by ligation of the left anterior coronary artery in 6-8 weeks-old male mice, which were fed Sto at a dose of 30 mg/kg/day for 4 weeks after surgery. The effects were assessed by echocardiography, histopathology, Langendorff Heart Perfusion System, ambulatory electrocardiography, and Western blot. In vitro experiments were performed to assess the effect of Sto on cardiomyocytes subjected to hypoxic.
Compared to the MI group, Sto treatment significantly improved cardiac function and reduced infarct size and fibrosis levels. Sto also decreased action potential duration (APD) and APD alternation thresholds. Ambulatory ECG and BURST stimulation showed that Sto reduced the incidence of VAs. In addition, Sto significantly improved the expression levels of ion channels and CX43 and ameliorated the abnormal expression of Ca2+ handling proteins after MI. Mechanistically, in vivo and in vitro experiments confirmed that TLR4/CaMKII activation was enhanced after MI, while Sto significantly inhibited the activation of the TLR4/CaMKII signaling pathway.
Sto improved LV remodeling and reduced the incidence of VAs after MI, which was regulated by modulating the TLR4/CaMKII signaling pathway.
心肌梗死后（MI）的室性心律失常（VA）是患者死亡的一个重要原因。抑制钠-葡萄糖协同转运蛋白 2（SGLT-2）已被证明可降低心肌梗死后的心血管死亡率，且不依赖于血糖变化，并可预防室性心律失常，但尚不清楚这些作用是否可以通过额外抑制 SGLT-1 得到进一步增强。我们研究了慢性使用双重 SGLT-1 和 2 抑制剂 sotagliflozin（Sto）对 MI 后 VA 及其潜在机制的影响。
在 6-8 周龄雄性小鼠中通过结扎左前冠状动脉诱导 MI，手术后给予小鼠 Sto 剂量为 30mg/kg/天，持续 4 周。通过超声心动图、组织病理学、Langendorff 心脏灌流系统、动态心电图和 Western blot 评估作用。进行体外实验评估 Sto 对缺氧状态下的心肌细胞的影响。
与 MI 组相比，Sto 治疗显著改善了心脏功能，减少了梗死面积和纤维化水平。Sto 还降低了动作电位时程（APD）和 APD 变化阈值。动态心电图和 BURST 刺激显示 Sto 降低了 VA 的发生率。此外，Sto 显著改善了 MI 后离子通道和 CX43 的表达水平，并改善了 Ca2+处理蛋白的异常表达。在机制上，体内和体外实验均证实 MI 后 TLR4/CaMKII 激活增强，而 Sto 显著抑制了 TLR4/CaMKII 信号通路的激活。
Sto 通过调节 TLR4/CaMKII 信号通路改善了 LV 重构，降低了 MI 后 VA 的发生率。
