Sex differences in TNFR2 signaling mechanisms following acute surgical ischemia

说明(申请人提供)：心脏手术患者体外循环后会发生心肌炎，并在缺血-再灌注(I/R)损伤后的心肌功能障碍中起关键作用。在心肌I/R损伤中存在性别差异(1)，最近的研究表明，由于对有害的肿瘤坏死因子受体1(TNFR1)信号的固有抵抗，女性对I/R具有更强的保护作用(2)。雌激素被认为是TNFR1信号耐受的媒介，但雌激素可能通过其他信号级联反应促进这些有益作用，包括上调血管生成因子，如血管生成因子。然而，肿瘤坏死因子受体2(TNFR2)在促进TNFR1信号耐受中可能发挥的作用尚不清楚。因此，我们假设：1)TNFR2介导I/R后的心肌恢复，对女性心肌功能、促炎细胞因子的产生和细胞凋亡信号的影响比男性更大；2)TNFR2通过产生血管内皮生长因子(VEGF)来增强女性的心肌保护；以及3)消融TNFR1和TNFR2将缩小心肌损伤后的性别差异。因此，本研究的具体目的是：1.确定TNFR2信号通路是否促进了缺血/再灌注后的功能恢复，如果是的话，TNFR2消融是否在更大程度上恶化了女性的心肌恢复。2.确定TNFR2消融是否增加了心肌组织中的肿瘤坏死因子、IL-1和IL-6；降低了血管内皮生长因子；增加了MARK信号(p38、ERK、MEK、JNK)，并在更大程度上增加了女性的促凋亡信号。3.确定同时消融两种肿瘤坏死因子受体1和2是否平衡了性别差异的功能。公共卫生相关性：女性在受伤后心脏功能较好。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.