Testosterone-down-regulated Akt pathway during cardiac ischemia/reperfusion: a mechanism involving BAD, Bcl-2 and FOXO3a.
Testosterone-down-regulated Akt pathway during cardiac ischemia/reperfusion: a mechanism involving BAD, Bcl-2 and FOXO3a.
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DOI：
10.1016/j.jss.2010.07.041
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发表时间：
2010-11
期刊：
影响因子：
--
通讯作者：
Wang M
中科院分区：
文献类型：
--
作者：
Huang C;Gu H;Zhang W;Herrmann JL;Wang M
男性心肌Akt活性水平较低与缺血/再灌注（I/R）后心力衰竭和心功能恶化的发生率较高相关。虽然雌激素激活Akt可提供女性的心脏保护作用，但没有关于I/R后睾酮对心肌Akt通路影响的信息。我们假设I/R后：1）内源性睾酮将降低雄性心脏中心肌Akt的激活; 2）内源性睾酮将介导Akt的下游信号，包括Bad、Bcl-2和FOXO 3a; 3）外源性睾酮的给药将重现对去势雄性心脏中Akt通路的负面影响。对来自年龄匹配的成年雄性、雌性、去势雄性、雄激素受体阻断剂-氟西汀雄性、长期植入5α-二氢睾酮（DHT）或急性睾酮输注（ATI）的去势雄性大鼠心脏（n=9/组）进行I/R（Langendorff）。去势或氟替卡松治疗显著上调心肌Akt激活，增加下游凋亡调节分子：p-Bad，Bcl-2，p-FOXO 3a，但减少Fas-L，与I/R后男性心脏心肌损伤减少一致。ATI的管理，但不是慢性DHT，逆转这些影响Akt信号与进一步恶化的心脏功能障碍，在去势男性。值得注意的是，在雄性心脏中观察到较低水平的MnSOD，并且在I/R后，去势或氟替卡松治疗使雄性心脏中的心肌MnSOD表达恢复到雌性的水平。我们的研究代表了I/R后雄性心脏中睾酮诱导Akt通路下调的初步证据，从而通过降低p-Bad、降低细胞质中Bcl-2/Bax的比率和增加细胞核中FOXO 3a介导心脏损伤。
Lower levels of myocardial Akt activity in males are associated with a higher incidence of heart failure and worsened cardiac function after ischemia/reperfusion (I/R). While Akt activation by estrogen provides cardioprotection in females, no information exists regarding the effect of testosterone on the myocardial Akt pathway following I/R. We hypothesized that following I/R: 1) endogenous testosterone will decrease myocardial Akt activation in male hearts; 2) endogenous testosterone will mediate downstream signals of Akt, including Bad, Bcl-2 and FOXO3a; 3) administration of exogenous testosterone will recapitulate negative effects on the Akt pathway in castrated male hearts. Rat hearts from age-matched adult males, females, castrated males, males with androgen receptor blocker-flutamide, castrated males with chronic 5α-dihydrotestosterone (DHT) implantation or acute testosterone infusion (ATI) (n=9/group) were subjected to I/R (Langendorff). Castration or flutamide treatment significantly upregulated myocardial Akt activation, increased downstream apoptosis-regulatory molecules: p-Bad, Bcl-2, p-FOXO3a, but reduced Fas-L, consistent with decreased myocardial injury in male hearts following I/R. ATI administration, but not chronic DHT, reversed these effects on Akt signaling associated with further exacerbated cardiac dysfunction in castrated males. Notably, lower levels of MnSOD were observed in male hearts, and castration or flutamide treatment restored myocardial MnSOD expression to the levels of females in male hearts after I/R. Our study represents the initial evidence of testosterone-induced downregulation of the Akt pathway in male hearts following I/R, thereby mediating cardiac injury through decreased p-Bad, reduced ratio of Bcl-2/Bax in the cytoplasm, and increased FOXO3a in the nucleus.
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