Abstract
Modulation of oxidative stress is therapeutically effective in ischemia/reperfusion (I/R) injury. Myricitrin, a naturally occurring phenolic compound, is a potent antioxidant. However, little is known about its effect on I/R injury to cardiac myocytes. The present study was performed to investigate the potential protective effect of myricitrin against hypoxia/reoxygenation (H/R)-induced H9c2 cardiomyocyte injury and its underlying mechanisms. Myricitrin pretreatment improved cardiomyocyte viability, inhibited ROS generation, maintained the mitochondrial membrane potential, reduced apoptotic cardiomyocytes, decreased the caspase-3 activity, upregulated antiapoptotic proteins and downregulated proapoptotic proteins during H/R injury. Moreover, the potential targets of myricitrin was predicted using Discovery Studio software, and heat shock protein 90 (Hsp90) was identified as the main disease-related target. Further mechanistic investigation revealed that 17-AAG, a pharmacologic inhibitor of Hsp90, significantly blocked the myricitrin-induced cardioprotective effect demonstrated by increased apoptosis and ROS generation. These results suggested that myricitrin provides protection to H9c2 cardiomyocytes against H/R-induced oxidative stress and apoptosis, most likely via increased expression of Hsp90.
Highlights
Myocardial ischemia/reperfusion (I/R) injury is the leading cause of morbidity and mortality after cardiac surgery and heart infarctions (Sharma et al, 2012)
Primary antibodies against heat shock protein 90 (Hsp90), Akt, and p-Akt were purchased from Abcam (Cambridge, United Kingdom)
The results of the present study clearly showed that Reactive oxygen species (ROS) production was well preserved as a result of myricitrin pretreatment during H/R; this effect was accompanied by significantly elevated activities of superoxide dismutase (SOD), GSH-Px, and CAT and decreased levels of MDA, suggesting that the cardioprotective effects of myricitrin against I/R are largely associated with its anti-oxidative capacity
Summary
Myocardial ischemia/reperfusion (I/R) injury is the leading cause of morbidity and mortality after cardiac surgery and heart infarctions (Sharma et al, 2012). Accumulating evidence from in vivo and in vitro studies strongly suggests that apoptosis is one of the major mechanisms of cardiomyocyte injury following hypoxia and ischemia–reperfusion (Lam et al, 2013). Reactive oxygen species (ROS) overproduction plays a crucial role in myocyte apoptosis during I/R injury (Takano et al, 2003). Hypoxia/reoxygenation (H/R) initiates the mitochondrial apoptotic pathway by inducing massive ROS production and the loss of mitochondrial membrane potential, which stimulates cytochrome c release and caspase-9 activation, and subsequent caspase-3 activation, resulting in apoptosis (Ryter et al, 2007). The inhibition of intracellular ROS levels and prevention of cardiomyocyte apoptosis are effective strategies to ameliorate myocardial I/R injury
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