Alberta Diabetes Institute (K.P., M.F., W.L., A.B., J.S., J.W., T.P., C.S., J.M.S., P.E.L.), University of Alberta, Edmonton, Canada.xs.
Department of Pharmacology (K.P., M.F., W.L., A.B., J.S., J.W., T.P., C.S., J.M.S., P.E.L.), University of Alberta, Edmonton, Canada.
Circulation. 2021 Jun;143(22):2188-2204. doi: 10.1161/CIRCULATIONAHA.121.053350. Epub 2021 Apr 9.
SGLT2 (sodium/glucose cotransporter 2) inhibitors exert robust cardioprotective effects against heart failure in patients with diabetes, and there is intense interest to identify the underlying molecular mechanisms that afford this protection. Because the induction of the late component of the cardiac sodium channel current (late-) is involved in the etiology of heart failure, we investigated whether these drugs inhibit late-.
Electrophysiological, in silico molecular docking, molecular, calcium imaging, and whole heart perfusion techniques were used to address this question.
The SGLT2 inhibitor empagliflozin reduced late- in cardiomyocytes from mice with heart failure and in cardiac Nav1.5 sodium channels containing the long QT syndrome 3 mutations R1623Q or ΔKPQ. Empagliflozin, dapagliflozin, and canagliflozin are all potent and selective inhibitors of HO-induced late- (half maximal inhibitory concentration = 0.79, 0.58, and 1.26 µM, respectively) with little effect on peak sodium current. In mouse cardiomyocytes, empagliflozin reduced the incidence of spontaneous calcium transients induced by the late- activator veratridine in a similar manner to tetrodotoxin, ranolazine, and lidocaine. The putative binding sites for empagliflozin within Nav1.5 were investigated by simulations of empagliflozin docking to a three-dimensional homology model of human Nav1.5 and point mutagenic approaches. Our results indicate that empagliflozin binds to Nav1.5 in the same region as local anesthetics and ranolazine. In an acute model of myocardial injury, perfusion of isolated mouse hearts with empagliflozin or tetrodotoxin prevented activation of the cardiac NLRP3 (nuclear-binding domain-like receptor 3) inflammasome and improved functional recovery after ischemia.
Our results provide evidence that late- may be an important molecular target in the heart for the SGLT2 inhibitors, contributing to their unexpected cardioprotective effects.
SGLT2（钠/葡萄糖共转运蛋白 2）抑制剂在糖尿病患者中对心力衰竭具有强大的心脏保护作用，人们强烈关注确定提供这种保护的潜在分子机制。由于心脏钠通道电流的晚期成分（晚期）的诱导与心力衰竭的病因有关，我们研究了这些药物是否抑制晚期。
使用电生理学、计算机分子对接、分子、钙成像和全心脏灌流技术来解决这个问题。
SGLT2 抑制剂恩格列净可减少心力衰竭小鼠的心肌细胞和含有长 QT 综合征 3 突变 R1623Q 或 ΔKPQ 的心脏 Nav1.5 钠通道中的晚期。恩格列净、达格列净和卡格列净都是 HO 诱导的晚期的有效且选择性抑制剂（半最大抑制浓度分别为 0.79、0.58 和 1.26 μM），对峰值钠电流几乎没有影响。在小鼠心肌细胞中，恩格列净以类似于河豚毒素、雷诺嗪和利多卡因的方式减少晚期激活剂维拉帕米诱导的自发钙瞬变的发生率。通过模拟恩格列净与人类 Nav1.5 的三维同源模型对接和定点突变方法，研究了恩格列净在 Nav1.5 中的假定结合位点。我们的结果表明，恩格列净与 Nav1.5 的结合部位与局部麻醉剂和雷诺嗪相同。在急性心肌损伤模型中，用恩格列净或河豚毒素灌流分离的小鼠心脏可防止心脏 NLRP3（核结合域样受体 3）炎性小体的激活，并改善缺血后的功能恢复。
我们的结果提供了证据，表明晚期可能是 SGLT2 抑制剂在心脏中的一个重要分子靶点，这有助于它们意想不到的心脏保护作用。
