Department of Pharmacology, Shantou University Medical College, Shantou 515041, China.
Department of Clinical Pharmacy, Shantou University Medical College, Shantou 515041, China.
Biomed Pharmacother. 2024 Nov;180:117568. doi: 10.1016/j.biopha.2024.117568. Epub 2024 Oct 13.
Apoptosis is a crucial pathological process in myocardial ischemia/reperfusion injury (MIRI). Verapamil (Ver), normally used to treat hypertension or heart rhythm disorders, also attenuates MIRI. The potential of Ver to inhibit apoptosis and thereby attenuate MIRI remains unclear, as does the mechanism. We established an in vivo mouse ischemia/reperfusion (I/R) model by occlusion of the left anterior descending coronary. To construct a hypoxia/reoxygenation model in vitro, H9c2 cardiomyocytes were immersed in a hypoxic buffer in a hypoxia/anaerobic workstation. Ver significantly improved cardiac function and reduced myocardial infarction size in I/R mice, while decreasing apoptosis. Both in vivo and in vitro, application of Ver activated the JAK2/STAT3 signaling pathway and elevated Bcl-2 expression, while decreasing Bax and cleaved caspase-3 levels. Treatment with AG490, a JAK2 inhibitor, partially counteracted the anti-apoptotic and the cardioprotective effect of Ver. Thus, we conclude that Ver alleviates MIRI by reducing apoptosis via the JAK2/STAT3 signaling pathway activation. These findings provide a novel mechanism of Ver in the treatment of MIRI.
细胞凋亡是心肌缺血/再灌注损伤（MIRI）中的一个关键病理过程。维拉帕米（Ver）通常用于治疗高血压或心律不齐，也能减轻 MIRI。Ver 抑制细胞凋亡从而减轻 MIRI 的潜力及其机制尚不清楚。我们通过结扎左前降支建立了体内小鼠缺血/再灌注（I/R）模型。为了在体外构建缺氧/复氧模型，将 H9c2 心肌细胞浸泡在缺氧缓冲液中在缺氧/厌氧工作站。Ver 显著改善 I/R 小鼠的心脏功能并减少心肌梗死面积，同时减少细胞凋亡。在体内和体外，Ver 的应用激活了 JAK2/STAT3 信号通路并提高了 Bcl-2 的表达，同时降低了 Bax 和 cleaved caspase-3 的水平。用 JAK2 抑制剂 AG490 处理部分抵消了 Ver 的抗凋亡和心脏保护作用。因此，我们得出结论，Ver 通过激活 JAK2/STAT3 信号通路减少细胞凋亡来减轻 MIRI。这些发现为 Ver 治疗 MIRI 的新机制提供了依据。
