? ? Myocardial ischemia is a leading cause of heart failure and death in both men and women. Restoration of blood flow to ischemic myocardium results in ischemia / reperfusion (I/R) injury. Sex-specific differences have been noted in myocardial I/R. Clinically, when compared to women, men experience: a higher overall incidence of heart failure, more rapid heart failure progression, worse age-matched cardiac contractility, and less preservation of myocardial mass as they age. These differences may be attributable to the effects of the sex hormone testosterone. Surprisingly, little information exists regarding the effect of testosterone on myocardial injury. Myocardial inflammation occurs following cardiac I/R injury and plays a crucial role in myocardial dysfunction. Tumor necrosis factor-alpha (TNF) is increased in myocardial tissue following I/R, and contributes to post-ischemic myocardial dysfunction, proinflammatory signaling and myocyte apoptosis. The effect of testosterone on TNFR1 and TNFR2 signaling following myocardial I/R remains unknown. Nearly simultaneously, ischemia results in the activation of JAK/STAT and p38 MARK signaling pathways, both of which are responsible for subsequent inflammatory cytokine production and apoptosis. Suppressors of cytokine signaling (SOCS) proteins, that are induced by various cytokines and stresses, exert negative effects on cytokine production and apoptosis. It remains unknown whether cross talk exists between the STAT/SOCS pathway and TNFR1 or TNFR2 signaling in the heart, and if so, whether testosterone amplifies ? or suppresses this link following myocardial I/R. A therapeutic approach to the treatment of heart failure ? may be to unbalance TNF signaling to diminish its deleterious effects while enhancing its salutary effects, towards a therapeutic benefit for both sexes. Utilizing endogenous mechanisms, such as SOCS mediated disruption of TNFR1 signaling, is appealing. We hypothesize that: 1) testosterone exacerbates acute myocardial ischemia and reperfusion injury by unbalancing TNFR1/TNFR2 signaling in favor of TNFR1; and 2) testosterone does so by disrupting the SOCS-3/STAT3 regulatory balance of TNFR1 signaling in the heart. Several specific aims are proposed to test these hypotheses which will be accomplished within the context of a detailed training plan, with the ultimate goal being a repeatedly-funded independent investigator at the faculty level. (End of Abstract) ? ? ?
