Testosterone in TNFR1 signaling during acute myocardial injury

急性心肌损伤期间睾酮在 TNFR1 信号传导中的作用

• 批准号: 7760646
• 负责人: Meijing Wang
• 金额: $ 24.9万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-01-23 至 2011-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7760646
• 关键词: Acute; Address; Age; Androgen Receptor; Apoptosis; Biological Preservation; Blood flow; Cardiac; Cardiac Myocytes; Castration; Cessation of life; Cytokine Inducible SH2-Containing Protein; Down-Regulation; Equilibrium; Female; Flutamide; Foundations; Gonadal Steroid Hormones; Heart; Heart failure; Hypoxia; Incidence; Inflammation; Infusion procedures; Injury; Ischemia; Knock-out; Knockout Mice; Link; Liposomes; Mediating; Methods; Molecular; Muscle Cells; Myocardial; Myocardial Ischemia; Myocardial dysfunction; Myocardial tissue; Pathway interactions; Phase; Play; Process; Production; Proteins; RNA Interference; Rattus; Recovery of Function; Regulation; Reperfusion Injury; Reperfusion Therapy; Research; Role; Signal Pathway; Signal Transduction; Signaling Protein; TNFRSF1B gene; Testosterone; The Sun; Therapeutic; Transducers; Tumor Necrosis Factor Receptor; Tumor Necrosis Factor-alpha; Up-Regulation; Update; Wild Type Mouse; Woman; base; cytokine; experience; improved; interest; male; men; response; restoration; sex

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.

我们的计划将与原计划相同。心肌缺血是心力衰竭的主要原因， 两性的死亡。缺血心肌血流恢复导致缺血/再灌注 （l/R）损伤。心肌I/R存在性别特异性差异。临床上，与 女性和男性经历：心力衰竭的总体发生率更高，心力衰竭进展更快， 随着年龄的增长，年龄匹配的心肌收缩力更差，肌管质量的保留更少。这些 差异可能归因于性激素睾酮的作用。令人惊讶的是，小 存在关于睾酮对心肌损伤的影响的信息。发生心肌炎症 在心脏I/R损伤后，其在心肌功能障碍中起关键作用。肿瘤坏死因子-α (TNF)在I/R后心肌组织中增加，并有助于缺血后心肌 功能障碍、促炎信号传导和肌细胞凋亡。睾酮对TNFR 1和TNFR 2的影响 心肌I/R后的TNFR 2信号传导仍然未知。此外，缺血导致激活 信号转导子和转录激活子3（STATS）通路，介导心肌炎症 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性影响， 生产和凋亡。我们的研究表明，串扰存在于 STAT 3/SOCS 3通路和TNFR 1或TNFR 2信号在经受I/R的心脏中的作用。但据 尚不清楚睾酮是否会增强或抑制心肌I/R后的这种联系。治疗心力衰竭的一种治疗方法可能是使TNF信号转导失衡，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STAT或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信号传导失衡而有利于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信号传导的SOCS 3/STAT 3调节平衡而这样做。