Role of endogenous testosterone in myocardial proinflammatory and proapoptotic signaling after acute ischemia-reperfusion
Role of endogenous testosterone in myocardial proinflammatory and proapoptotic signaling after acute ischemia-reperfusion
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DOI：
10.1152/ajpheart.00784.2004
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发表时间：
2005-01-01
影响因子：
4.8
通讯作者：
Meldrum, DR
中科院分区：
文献类型：
--
作者：
Wang, MJ;Tsai, BM;Meldrum, DR
心肌缺血是男性和女性死亡的主要原因;然而，关于睾酮对心肌对急性缺血性损伤的反应的影响的信息很少。我们假设睾酮可能对急性缺血再灌注（I/R）后心肌炎性细胞因子的产生、p38 MAPK活化、凋亡信号传导和心肌功能恢复产生有害影响。为了研究这一点，将来自成年雄性、去势雄性和用睾酮受体阻断剂（氟替卡松）处理的雄性的分离的灌注大鼠心脏（Langendorff）进行25分钟的缺血，随后进行40分钟的再灌注。连续记录心肌收缩功能（左室发展压、左室舒张末压、压力的正负一阶导数）。再灌注后，分析心脏组织TNF-α、IL-1 β和IL-6的表达（ELISA）和p38 MAPK、caspase-1、caspase-3、caspase-11和Bcl-2的活化（Western印迹）。与未处理雄性动物相比，去势雄性动物或氟他胺处理雄性动物的缺血后心肌功能恢复的所有指标均显著较高。I/R后，去势雄性和氟他胺处理的雄性心脏与未处理的雄性相比，TNF-α、IL-1 β和IL-6降低;活化p38 MAPK降低; caspase-1、caspase-3和caspase-11降低; Bcl-2表达增加。这些结果表明，在正常男性中，阻断睾酮受体（氟替卡松）或消耗睾酮（去势）可改善I/R后的心肌功能。这些作用可能归因于内源性睾酮的促炎和/或促凋亡特性。进一步的理解可能允许在急性I/R的治疗中对性激素信号传导机制进行治疗性操纵。
Myocardial ischemia is the leading cause of death in both men and women; however, very little information exists regarding the effect of testosterone on the response of myocardium to acute ischemic injury. We hypothesized that testosterone may exert deleterious effects on myocardial inflammatory cytokine production, p38 MAPK activation, apoptotic signaling, and myocardial functional recovery after acute ischemia-reperfusion (I/R). To study this, isolated, perfused rat hearts (Langendorff) from adult males, castrated males, and males treated with a testosterone receptor blocker (flutamide) were subjected to 25 min of ischemia followed by 40 min of reperfusion. Myocardial contractile function ( left ventricular developed pressure, left ventricular end-diastolic pressure, positive and negative first derivative of pressure) was continuously recorded. After reperfusion, hearts were analyzed for expression of tissue TNF-alpha, IL-1beta, and IL-6 (ELISA) and activation of p38 MAPK, caspase-1, caspase-3, caspase-11, and Bcl-2 (Western blot). All indices of postischemic myocardial functional recovery were significantly higher in castrated males or flutamide-treated males compared with untreated males. After I/R, castrated male and flutamide-treated male hearts had decreased TNF-alpha, IL-1beta, and IL-6; decreased activated p38 MAPK; decreased caspase-1, caspase-3, and caspase-11; and increased Bcl-2 expression compared with untreated males. These results show that blocking the testosterone receptor ( flutamide) or depleting testosterone ( castration) in normal males improves myocardial function after I/R. These effects may be attributed to the proinflammatory and/or the proapoptotic properties of endogenous testosterone. Further understanding may allow therapeutic manipulation of sex hormone signaling mechanisms in the treatment of acute I/R.