Testosterone in TNFR1 signaling during acute myocardial injury

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Our project will be the same as the original plan. Myocardial ischemia is a leading cause of heart failure and death in both sexes. Restoration of blood flow to ischemic myocardium results In ischemia / reperfusion (l/R) injury. Sex-specific differences have been noted in myocardial l/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 myocanJial 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 l/R injury and plays a crucial role in myocardial dysfunction. Tumor necrosis factor-alpha (TNF) is increased in myocardial tissue following l/R, and contributes to post-ischemic myocardial dysfunction, proinflammatory signaling and myocyte apoptosis. The effect of testosterone on TNFR1 and TNFR2 signaling following myocardial l/R remains unknown. In addition, ischemia results in the activation of signal transducer and activator of transcription3 (STATS) pathway, which mediates myocardial inflammation and myocyte sun/ivaj. Suppressors of cytokine signaling (SOCS) proteins exert negative effects on cytokine production and apoptosis. Our studies have demonstrated that cross-talk existed between the STAT3/SOCS3 pathway and TNFR1 or TNFR2 signaling in the heart subjected to l/R. However, it is unknown whether testosterone amplifies or suppresses this link following myocardial l/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 STAT or SOCS mediated disruption of TNFR1 signaling, is appealing. We hypothesize that: 1) testosterone exaceriiates acute myocardial ischemia and reperfusion injury by unbalancing TNFR1/TNFR2 signaling in favor of TNFR1; and 2) testosterone does so by disrupting the SOCS3/STAT3 regulatory balance of TNFR1 signaling in the heart.