Testosterone in TNFR1 signaling during acute myocardial injury

我们的项目将与原计划相同。心肌缺血是心力衰竭的主要原因， 男性和女性都死亡。缺血心肌血流恢复可导致缺血/再灌流 (L/R)受伤。在临床上，与L/R相比，心肌梗死患者中存在性别差异。 女性和男性经历：心力衰竭的总体发病率更高，心力衰竭进展更快， 与年龄匹配的心肌收缩能力更差，随着年龄的增长，心肌质量的保存更少。这些 差异可能归因于性激素睾丸素的影响。令人惊讶的是，几乎没有 关于睾酮对心肌损伤的影响的信息已经存在。发生心肌炎 在心脏L/再灌注损伤后，并在心肌功能障碍中起关键作用。肿瘤坏死因子-α L缺血再灌注后心肌组织中肿瘤坏死因子升高，参与缺血后心肌组织的损伤。 功能障碍、促炎信号和心肌细胞凋亡。睾酮对肿瘤坏死因子受体1及受体表达的影响 心肌L/再灌注后的肿瘤坏死因子受体2信号转导机制尚不清楚。此外，缺血还会导致心肌细胞激活 介导心肌炎症的信号转导和转录激活子3(STATS)通路 和肌细胞SUN/IVAJ。细胞因子信号转导抑制因子(SOCS)蛋白对细胞因子产生负面影响 生产和细胞凋亡。我们的研究已经证明，串扰存在于 L/再灌注心脏中STAT3/SOCS3通路和TNFR_1或TNFR_2信号转导途径的研究 目前尚不清楚睾酮是增强还是抑制了心肌L/再灌注后的这种联系。治疗心力衰竭的一种治疗方法可能是失衡肿瘤坏死因子信号，以减少其有害作用，同时增强其有益作用，从而实现对两性的治疗益处。利用内源性机制，如STAT或SOCS介导的TNFR1信号的中断，是很有吸引力的。 我们假设：1)睾酮通过破坏有利于TNFR1的TNFR1/TNFR2信号的平衡而导致急性心肌缺血和再灌注损伤；2)睾酮通过破坏心脏中TNFR1信号的SOCS3/STAT3调节平衡来实现这一点。

Our project will be the same as the original plan. Myocardial ischemia is a leading cause of heart failure and death in both sexes. Restoration of blood flow to ischemic myocardium results In ischemia / reperfusion (l/R) injury. Sex-specific differences have been noted in myocardial l/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 myocanJial 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 l/R injury and plays a crucial role in myocardial dysfunction. Tumor necrosis factor-alpha (TNF) is increased in myocardial tissue following l/R, and contributes to post-ischemic myocardial dysfunction, proinflammatory signaling and myocyte apoptosis. The effect of testosterone on TNFR1 and TNFR2 signaling following myocardial l/R remains unknown. In addition, ischemia results in the activation of signal transducer and activator of transcription3 (STATS) pathway, which mediates myocardial inflammation and myocyte sun/ivaj. Suppressors of cytokine signaling (SOCS) proteins exert negative effects on cytokine production and apoptosis. Our studies have demonstrated that cross-talk existed between the STAT3/SOCS3 pathway and TNFR1 or TNFR2 signaling in the heart subjected to l/R. However, it is unknown whether testosterone amplifies or suppresses this link following myocardial l/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 STAT or SOCS mediated disruption of TNFR1 signaling, is appealing. We hypothesize that: 1) testosterone exaceriiates acute myocardial ischemia and reperfusion injury by unbalancing TNFR1/TNFR2 signaling in favor of TNFR1; and 2) testosterone does so by disrupting the SOCS3/STAT3 regulatory balance of TNFR1 signaling in the heart.