Sex-specific p38 MAP kinase activation in myocardial ischemia reperfusion injury in dogs

ABSTRACT

Very little information exists concerning the influence of sex on the response of the myocardium itself to an acute insult such as ischemia-reperfusion [I/R]. It was suggested that differences in the activation of p38 may mediate the sex-related difference in myocardial signaling after I-R which may contribute to the lower incidence of cardiac complications in females after myocardial ischemia. To evaluate the effect of sex hormones on the activation of p38 MAP kinase in a canine model of ischemia reperfusion injury. This study was conducted on 42 adult dogs of both sexes, they were classified into three groups. The first group [group I] contained 14 male dogs, the second group [group II] included 14 cycling female dogs and the third one [group III] consisted of 14 female dogs which were ovariectomized 3 weeks prior to experiment. Each group was subdivided randomly into 2 equal subgroups, I/R group [n=7] and control group [n=7]. The myocardial I/R model included anesthesized open-chest dogs after 25 minutes occlusion of the left anterior descending coronary artery [LAD] and subsequent reperfusion. Myocardial p38 MAPK and TNF-alpha and serum estrogen as well as testosterone were measured. The present study revealed decreased levels of p38 and TNF- alpha levels in the hearts of female dogs compared to male dogs and ovariectomized females subjected to the same I/R injury, suggesting that sex differences may exist in the p38 MAPK signaling pathway and cytokine response. Our findings indicate that sex difference exists in the myocardial response to acute I/R, where females dogs showed some degree of myocardial protection than males and ovariectomized females. Endogenous estrogen may be partly responsible for this cardioprotective effect by lowering p38 MAPK activation and subsequent decrease in TNF-alpha production and this benificial effect is lost in ovariectomized females. In addition, the study confirmed the deleterious effects of testosterone on myocardium through activation ofp38 MAPK and the resulting increase in TNF- alpha production