Testosterone in TNFR1 Signaling During Acute Myocardial Injury

描述（由申请人提供）： 心肌缺血是男性和女性心力衰竭和死亡的主要原因。缺血心肌血流的恢复导致缺血/再灌注（I/R）损伤。心肌I/R存在性别差异。临床上，与女性相比，男性经历：心力衰竭的总体发生率更高，心力衰竭进展更快，年龄匹配的心肌收缩力更差，随着年龄的增长心肌质量的保留更少。这些差异可能是由于性激素睾酮的影响。令人惊讶的是，关于睾酮对心肌损伤的影响的信息很少。心肌炎症反应发生于心脏I/R损伤后，在心肌功能障碍中起着至关重要的作用。肿瘤坏死因子-α（TNF）在I/R后心肌组织中增加，并且有助于缺血后心肌功能障碍、促炎信号传导和心肌细胞凋亡。 睾酮对心肌I/R后TNFR 1和TNFR 2信号传导的影响尚不清楚。 几乎同时，缺血导致JAK/STAT和p38 MARK信号通路的激活，这两者都负责随后的炎性细胞因子产生和细胞凋亡。细胞因子信号转导抑制因子（SOCS）蛋白是由各种细胞因子和应激诱导的，对细胞因子的产生和细胞凋亡产生负面影响。目前尚不清楚STAT/SOCS通路与心脏中的TNFR 1或TNFR 2信号之间是否存在串扰，如果存在，睾酮是否会放大 或在心肌I/R后抑制这种联系。心力衰竭的治疗方法 可能是为了平衡TNF信号传导，以减少其有害作用，同时增强其有益作用，从而对两性都有治疗益处。利用内源性机制，如SOCS介导的TNFR 1信号转导的破坏，是有吸引力的。我们假设：1）睾酮通过使TNFR 1/TNFR 2信号失衡而有利于TNFR 1而加剧急性心肌缺血和再灌注损伤;和2）睾酮通过破坏心脏中TNFR 1信号的SOCS-3/STAT 3调节平衡而这样做。提出了几个具体的目标，以测试这些假设，这将在一个详细的培训计划的背景下完成，最终目标是一个反复资助的独立调查员在教师一级。 (End摘要）

DESCRIPTION (provided by applicant): Myocardial ischemia is a leading cause of heart failure and death in both men and women. Restoration of blood flow to ischemic myocardium results in ischemia / reperfusion (I/R) injury. Sex-specific differences have been noted in myocardial I/R. Clinically, when compared to women, men experience: a higher overall incidence of heart failure, more rapid heart failure progression, worse age-matched cardiac contractility, and less preservation of myocardial mass as they age. These differences may be attributable to the effects of the sex hormone testosterone. Surprisingly, little information exists regarding the effect of testosterone on myocardial injury. Myocardial inflammation occurs following cardiac I/R injury and plays a crucial role in myocardial dysfunction. Tumor necrosis factor-alpha (TNF) is increased in myocardial tissue following I/R, and contributes to post-ischemic myocardial dysfunction, proinflammatory signaling and myocyte apoptosis. The effect of testosterone on TNFR1 and TNFR2 signaling following myocardial I/R remains unknown. Nearly simultaneously, ischemia results in the activation of JAK/STAT and p38 MARK signaling pathways, both of which are responsible for subsequent inflammatory cytokine production and apoptosis. Suppressors of cytokine signaling (SOCS) proteins, that are induced by various cytokines and stresses, exert negative effects on cytokine production and apoptosis. It remains unknown whether cross talk exists between the STAT/SOCS pathway and TNFR1 or TNFR2 signaling in the heart, and if so, whether testosterone amplifies or suppresses this link following myocardial I/R. A therapeutic approach to the treatment of heart failure may be to unbalance TNF signaling to diminish its deleterious effects while enhancing its salutary effects, towards a therapeutic benefit for both sexes. Utilizing endogenous mechanisms, such as SOCS mediated disruption of TNFR1 signaling, is appealing. We hypothesize that: 1) testosterone exacerbates acute myocardial ischemia and reperfusion injury by unbalancing TNFR1/TNFR2 signaling in favor of TNFR1; and 2) testosterone does so by disrupting the SOCS-3/STAT3 regulatory balance of TNFR1 signaling in the heart. Several specific aims are proposed to test these hypotheses which will be accomplished within the context of a detailed training plan, with the ultimate goal being a repeatedly-funded independent investigator at the faculty level. (End of Abstract)