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TRANSLATIONAL PHYSIOLOGY

Brief exposure to exogenous testosterone increases death signaling and adversely affects myocardial function after ischemia

Departments of ¹Surgery, ²Cellular and Integrative Physiology, and the ³Center for Immunobiology, Indiana University School of Medicine, Indianapolis, Indiana

Submitted 29 November 2005 ; accepted in final form 17 January 2006

ABSTRACT

Chronic endogenous testosterone exposure adversely affects proinflammatory and proapoptotic signaling after ischemia/reperfusion; however, it remains unknown whether a single acute testosterone exposure is equally detrimental. We hypothesized that acute exogenous testosterone infusion before ischemia would worsen myocardial functional recovery, increase the activation of MAPKs and caspase-3, and increase myocardial proinflammatory cytokine production. To study this, isolated-perfused rat hearts (Langendorff) from adult females and castrated males were subjected to 25-min ischemia and 40-min reperfusion with and without acute testosterone infusion (17-hydroxy-4-androstenone, 10 ng·ml^–1·min^–1) before ischemia. Myocardial contractile function was continuously recorded. After ischemia/reperfusion, hearts were assessed for levels of testosterone (ELISA), expression of proinflammatory cytokines (ELISA), and activation of MAPKs and caspase-3 (Western blot analysis). Data were analyzed with two-way ANOVA or Student’s t-test; P < 0.05 was statistically significant. All indices of postischemic functional recovery were decreased with acute exogenous testosterone compared with the untreated groups. Acute testosterone infusion increased activation of MAPKs and caspase-3 following ischemia/reperfusion. However, there were no significant differences in the myocardial proinflammatory cytokine production after brief testosterone infusion. A single acute exposure to exogenous testosterone before ischemia worsens myocardial functional recovery and increases activation of MAPKs and caspase-3. These findings confirm the deleterious effects of testosterone on myocardium, elucidate the nongenomic mechanistic pathways of testosterone, and may have important clinical implications for patients who have acute exposure to exogenous testosterone.

myocardial infarction; sex hormones; inflammation

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