Bao Mi, Huang Weiyi, Zhao Yang, Fang Xinzhe, Zhang Yanmei, Gao Fenfei, Huang Danmei, Wang Bin, Shi Ganggang
Department of Pharmacology, Shantou University Medical College, Shantou, China.
Department of Clinical Pharmacy, Shantou University Medical College, Shantou, China.
Front Pharmacol. 2022 Feb 23;13:822640. doi: 10.3389/fphar.2022.822640. eCollection 2022.
Myocardial ischemia/reperfusion (I/R) injury is a potential complication of ischemic heart disease after recanalization. One of the primary reasons for I/R injury is the excessive accumulation of reactive oxygen species (ROS) in cardiomyocytes. Verapamil, a classic calcium channel blocker, has the potential to mitigate I/R-evoked oxidative stress. However, the underlying mechanisms have not been fully elucidated. SIRT1 is an essential regulator of I/R and offers resistance to oxidative stress arising from I/R. It is still inconclusive if verapamil can reduce myocardial I/R-triggered oxidative damage through modulating SIRT1 antioxidant signaling. To verify our hypothesis, the H9c2 cardiomyocytes and the mice were treated with verapamil and then exposed to hypoxia/reoxygenation (H/R) or I/R in the presence or absence of the SIRT1 inhibitor EX527. As expected, verapamil stimulated SIRT1 antioxidant signaling evidenced by upregulation of SIRT1, FoxO1, SOD2 expressions and downregulation of Ac-FoxO1 expression and . In addition, verapamil remarkably suppressed H/R and I/R-induced oxidative stress proven by declined ROS level and MDA content. The cardioprotective actions of verapamil via SIRT1 were further confirmed in the experiments with the presence of the specific SIRT1 inhibitor EX527. We demonstrated that verapamil alleviated myocardial I/R-evoked oxidative stress partially via activation of SIRT1 antioxidant signaling. Subsequently, verapamil protected against cardiac dysfunction and myocardial infarction accompanied by oxidative stress.
心肌缺血/再灌注（I/R）损伤是缺血性心脏病再灌注后的一种潜在并发症。I/R损伤的主要原因之一是心肌细胞中活性氧（ROS）的过度积累。维拉帕米是一种经典的钙通道阻滞剂，具有减轻I/R诱发的氧化应激的潜力。然而，其潜在机制尚未完全阐明。SIRT1是I/R的重要调节因子，可抵抗I/R引起的氧化应激。维拉帕米是否能通过调节SIRT1抗氧化信号通路来减少心肌I/R引发的氧化损伤仍无定论。为了验证我们的假设，将H9c2心肌细胞和小鼠用维拉帕米处理，然后在有或没有SIRT1抑制剂EX527的情况下暴露于缺氧/复氧（H/R）或I/R。正如预期的那样，维拉帕米刺激了SIRT1抗氧化信号通路，表现为SIRT1、FoxO1、SOD2表达上调和Ac-FoxO1表达下调。此外，维拉帕米显著抑制了H/R和I/R诱导的氧化应激，表现为ROS水平和MDA含量下降。在存在特异性SIRT1抑制剂EX527的实验中，进一步证实了维拉帕米通过SIRT1发挥的心脏保护作用。我们证明，维拉帕米部分通过激活SIRT1抗氧化信号通路减轻心肌I/R诱发的氧化应激。随后，维拉帕米预防了伴有氧化应激的心脏功能障碍和心肌梗死。
