Verapamil Alleviates Myocardial Ischemia/Reperfusion Injury by Attenuating Oxidative Stress via Activation of SIRT1

Abstract

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 in vitro and in vivo. 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.

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“…Similar to real oxygen deprivation, treating with CoCl 2 induces oxidative stress and mitochondrial DNA damage [33]. Various investigations found that chronic low oxygen level or hypoxia/reoxygenation conditions results in a significant increase in ROS level in H9c2 cells [34,35]. It is considered that the decrease in the activity of the mitochondrial electron transport chain during hypoxia slows down electron transfer, increasing the likelihood of an undesired electron transition to molecular oxygen, which produces a highly efficient reactive superoxide anion (O 2− ) [36].…”

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“…Global I/R surgery was prepared as previously described 23 . Following 1‐week adaption, one single dose of sodium pentobarbital (50 mg/kg) was intraperitoneally injected to mice to induce general anaesthesia.…”

“…Global I/R surgery was prepared as previously described. 23 Following 1-week adaption, one single dose of sodium pentobarbital (50 mg/kg) was intraperitoneally injected to mice to induce general anaesthesia. After complete anaesthesia, mice were intubated and connected to a rodent ventilator to ensure effective ventilation.…”

“…Echocardiography (ECG) was carried out to estimate the heart function by the Vevo 2100 imaging system (Visual Sonics Inc., Toronto, Ontario, Canada) as previously described. 23 After mild anaesthesia using isoflurane, different groups of mice underwent transthoracic ECG to acquire high-resolution echocardiographic images using 30-MHz probe. The images were applied to measure a battery of indices of left ventricular function.…”