Sex differences in TNFR2 signaling mechanisms following acute surgical ischemia

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DESCRIPTION (provided by applicant): Myocardial inflammation occurs following cardiopulmonary bypass in patients undergoing cardiac surgery and plays a crucial role in myocardial dysfunction following ischemia-reperfusion (I/R) injury. Gender disparities exist in myocardial I/R injury (1), and recent studies suggest that females exhibit enhanced protection from I/R due to an inherent resistance in detrimental TNF receptor 1 (TNFR1) signaling (2). Estrogen has been implicated as a mediator of TNFR1 signaling resistance, but it is likely that estrogen facilitates these beneficial effects through other signaling cascades, including the upregulation of angiogenic factors such as VEGF. The role that TNF receptor 2 (TNFR2) may play in facilitating TNFR1 signaling resistance, however, has yet to be elucidated. We therefore hypothesize that: 1) TNFR2 mediates myocardial recovery after I/R, and has a greater impact on myocardial function, proinflammatory cytokine production, and apoptotic signaling in females as compared to males; 2) TNFR2 mediates increased myocardial protection in females through the production of vascular endothelial growth factor (VEGF); and 3) ablation of both TNFR1 and TNFR2 will equalize gender differences seen after myocardial injury. Therefore, the specific aims of this study are to: 1. determine whether improved functional recovery after ischemia/reperfusion is mediated by TNFR2 signaling, and if so, whether TNFR2 ablation worsens myocardial recovery to a greater degree in females 2. Determine if TNFR2 ablation increases myocardial TNF, IL-1, and IL-6; decreases VEGF; increases MARK signaling (p38, ERK, MEK, JNK), and increases proapoptotic signaling to a greater degree in females 3. determine if simultaneous ablation of both TNF receptors 1 and 2 equalizes gender differences in function. PUBLIC HEALTH RELEVANCE: Females have better heart function after injury. Therefore, by understanding the signals that female heart cells use to improve their function after injury, we may be able to design new drugs and therapies to treat heart disease in both men and women.