TNFR1 and Sex Hormone Signaling in Myocardial Ischemia

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DESCRIPTION (provided by applicant): Inflammatory cytokines have been implicated in the pathogenesis of myocardial injury following acute surgical ischemia. Sex hormones have a profound influence over inflammatory processes. Indeed, clinical outcomes appear to be influenced by patient gender; however, the available clinical data are mixed. To the extent that proinflammatory signaling contributes to injury, estrogen's (and/or testosterone's) effects on these signaling processes may in part explain differences in outcomes, but more importantly may provide insight into potential therapeutic strategies. Based on the apparent weight of the clinical data, we first hypothesized that estrogen would provoke acute inflammation in the heart, and thereby worsen recovery. Our preliminary data did not support that hypothesis. Based on the background of our published findings, as well as the findings of others, our hypothesis is TNFR1 signaling resistance occurs in females by estrogen receptor alpha dependent intracellular signaling crosstalk with the TNFR1 signaling. As significant advancements towards this goal we will: 1) determine the effect of gender and endogenous testosterone or estrogen on myocardial proinflammatory signaling activity (e.g. p38 MAPK activity) and cytokine (TNF-alpha, IL-1beta, IL-6) production after I/R in wild type males and females and TNFR1 knockout males and females; 2) determine the effect of testosterone on TNF receptor(s) mediated myocardial dysfunction following I/R and define the role of TNF inhibition in downstream cytokine (IL-1, IL-6) production and TNF auto-amplification; 3) Measure the effect of TNFR1 and sex hormones on apoptotic signaling via Apaf-1, caspase-9, -8 and -3 production in male and female hearts subjected to endogenous testosterone or estrogen depletion and replacement.