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. ? ? ?
| Markel, Troy A; Crisostomo, Paul R; Manukyan, Maiuxi C et al. (2009) Are neonatal stem cells as effective as adult stem cells in providing ischemic protection? J Surg Res 152:325-30 |
| Novotny, Nathan M; Lahm, Tim; Markel, Troy A et al. (2009) Angiopoietin-1 in the treatment of ischemia and sepsis. Shock 31:335-41 |
| Erwin, Graham S; Crisostomo, Paul R; Wang, Yue et al. (2009) Estradiol-treated mesenchymal stem cells improve myocardial recovery after ischemia. J Surg Res 152:319-24 |
| Zeller, Courtney N; Wang, Yue; Markel, Troy A et al. (2009) Role of tumor necrosis factor receptor 1 in sex differences of stem cell mediated cardioprotection. Ann Thorac Surg 87:812-9 |
| Weil, Brent R; Markel, Troy A; Herrmann, Jeremy L et al. (2009) Mesenchymal stem cells enhance the viability and proliferation of human fetal intestinal epithelial cells following hypoxic injury via paracrine mechanisms. Surgery 146:190-7 |
| Novotny, Nathan M; Lahm, Tim; Markel, Troy A et al. (2009) beta-Blockers in sepsis: reexamining the evidence. Shock 31:113-9 |
| Wang, Meijing; Crisostomo, Paul R; Markel, Troy et al. (2008) Estrogen receptor beta mediates acute myocardial protection following ischemia. Surgery 144:233-8 |
| Ray, Rinki; Novotny, Nathan M; Crisostomo, Paul R et al. (2008) Sex steroids and stem cell function. Mol Med 14:493-501 |
| Crisostomo, Paul R; Markel, Troy A; Wang, Yue et al. (2008) Surgically relevant aspects of stem cell paracrine effects. Surgery 143:577-81 |
| Markel, Troy A; Wairiuko, George M; Lahm, Tim et al. (2008) The right heart and its distinct mechanisms of development, function, and failure. J Surg Res 146:304-13 |
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