Gender Differences in Cardioprotection against Ischemia/Reperfusion Injury in Adult Rat Hearts: Focus on Akt and Protein Kinase C Signaling

Abstract

Previous studies have reported the sex differences in heart susceptibility to ischemia/reperfusion (I/R) injury, but the mechanisms are not understood. The present study tested the hypothesis that Akt and protein kinase C (PKC)⑀ play an important role in the sexual dimorphism of heart susceptibility to I/R injury. Isolated hearts from 2-month-old male and female rats were subjected to I/R in the Langendorff preparation. The postischemic recovery of left ventricular function was significantly better, and infarct size was significantly smaller in female (37.1 Ϯ 1.9%) than in male (48.3 Ϯ 2.3%) hearts after 25-min ischemia followed by 2-h reperfusion. Inhibition of phosphatidylinositol 3-kinase/Akt pathway by wortmannin or PKC by chelerythrine chloride before ischemia significantly reduced postischemic recovery and increased infarct size in female but not male hearts. There were no differences in myocardial protein levels of heat shock protein 70, Akt, and PKC⑀, respectively, between male and female rats. However, the ratio of phosphorylated (p)-Akt/Akt (0.58 Ϯ 0.05 versus 0.22 Ϯ 0.04; P Ͻ 0.05) and p-PKC⑀/PKC⑀ (0.35 Ϯ 0.03 versus 0.22 Ϯ 0.02; P Ͻ 0.05) was significantly higher in female than in male hearts. In addition, there were significant increases in p-Akt and p-PKC⑀ levels during reperfusion in female but not in male hearts. The results suggest that increased p-Akt and p-PKC⑀ levels in female hearts contribute to the gender-related differences in heart susceptibility to I/R and play an important role in cardioprotection against I/R injury in females.It is becoming increasingly appreciated that gender differences exist in susceptibility to and mortality from a variety of cardiovascular diseases (Leinwand, 2003). Recent studies have suggested that there are gender differences in the myocardial response to acute ischemia and reperfusion injury. It has been shown in animal models that female hearts have greater resistance to ischemia and reperfusion-mediated injury in the Langendorff preparation, with reduced myocardial infarct size (Wang et al., 2005). In addition, cardiomyocytes from female hearts have been shown to be more resistant to ischemia and reperfusion injury compared with male cardiomyocytes (Ranki et al., 2001). Studies of ovariectomized rats and estrogen replacement have suggested that estrogen plays an important role in the cardioprotection of global ischemia and reperfusion injury in female hearts (Zhai et al., 2000). However, the mechanisms underlying the gender dimorphism in heart susceptibility to ischemia and reperfusion injury are not completely understood.During ischemic disease, the heart can benefit from protective measures from an endogenous source. Several mechanisms have been proposed to protect the heart from ischemia and reperfusion injury. For example, it has been demonstrated in both cultured cardiomyocytes and the intact heart of experimental animal models that heat shock protein (HSP) 70 plays an important role in the protection against ischemia and that the degree of the...

Estrogen, NFκB, and the Heat Shock Response

“…In I/R models, intact premenopausal female rodents compared with males have reduced injury as evidenced by smaller infarct size and greater recovery after I/R (16,17). Acute and/or chronic E2 supplementation provided protection both in isolated perfused hearts undergoing global ischemia and in in vivo ligation of the left anterior descending coronary artery (18,19).…”

“…Acute and/or chronic E2 supplementation provided protection both in isolated perfused hearts undergoing global ischemia and in in vivo ligation of the left anterior descending coronary artery (18,19). The exact mechanism is unknown, but it has been shown that females exhibit greater activation of AKT and protein kinase C (PKC) epsilon, and inhibition of either of these pathways led to the loss of protection in females, but had no effect on males (20). Both ER α and β have been shown to mediate the protective effects in I/R injury (21,22).…”

Models of gender differences in cardiovascular disease

“…For example, in an in vitro, global ischemia-reperfusion model using Langendorff-perfused rat hearts, Bae and Zhang observed significantly less myocardial injury in female vs. male hearts (23% relative reduction) following 25 minutes of ischemia and 2 hours of reperfusion. [22] Pharmacologic inhibitor experiments further showed that reduced myocardial injury in females was dependent on the phosphatidylinositol-3 kinase and protein kinase C epsilon (PKCε) signaling pathways. Brown et al [23] demonstrated in a similar model that protection from injury in females was dependent on functional sarcolemmal K ATP channels.…”

Long-Term Treatment With San’o-Shashin-To, a Kampo Medicine, Markedly Ameliorates Cardiac Ischemia-Reperfusion Injury in Ovariectomized Rats via the Redox-Dependent Mechanism

“…It has been elucidated in rats that females have greater resistance to cardiac IR injury than males through the effect of estrogen, 29 and that treatment with estrogen mitigates cardiac IR injury in ovariectomized rats. 30 In the present study, longterm treatment with TJ-113 did not affect plasma estrogen levels in the ovariectomized rats, suggesting that the beneficial effects of TJ-113 on the IR injury in the ovariectomized rats were not related to changes in plasma estrogen levels.…”