Sex differences in TNFR2 signaling mechanisms following acute surgical ischemia

描述（由申请人提供）：心脏手术患者体外循环术后发生心肌炎症，在缺血再灌注（I/R）损伤后心肌功能障碍中起关键作用。心肌I/R损伤存在性别差异(1)，最近的研究表明，由于有害的TNF受体1 （TNFR1）信号固有抵抗，女性对I/R的保护能力增强(2)。雌激素被认为是TNFR1信号抗性的中介，但雌激素可能通过其他信号级联促进这些有益作用，包括血管生成因子如VEGF的上调。然而，TNF受体2 （TNFR2）在促进TNFR1信号抗性中的作用尚未阐明。因此，我们假设：1)TNFR2介导I/R后心肌恢复，并且与男性相比，TNFR2对女性心肌功能、促炎细胞因子产生和凋亡信号传导的影响更大；2) TNFR2通过产生血管内皮生长因子（VEGF）介导女性心肌保护增强；3)同时消融TNFR1和TNFR2可以平衡心肌损伤后的性别差异。因此，本研究的具体目的是：1。确定缺血/再灌注后功能恢复的改善是否由TNFR2信号介导，如果是，TNFR2消融是否在更大程度上恶化女性心肌恢复2。确定TNFR2消融是否增加心肌TNF、IL-1和IL-6；降低VEGF;增加MARK信号（p38， ERK， MEK， JNK），并在雌性中更大程度地增加促凋亡信号3。确定同时消融TNF受体1和2是否能平衡功能上的性别差异。公共卫生相关性：女性损伤后心脏功能更好。因此，通过了解女性心脏细胞在受伤后用来改善其功能的信号，我们可能能够设计新的药物和疗法来治疗男性和女性的心脏病。

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.