Abstract 3004: Testosterone Mediates Myocardial Down-regulation of Akt/PI3k Activation and Increases Cardiomyocyte Injury Following Acute Ischemia/Reperfusion
Introduction: PI3K/Akt signaling is cardioprotective. Compared to females, males have lower levels of myocardial Akt activity associated with a higher incidence of heart failure and worsened cardiac function after ischemia/reperfusion (I/R). Studies have shown that Akt activation by estrogen provides cardioprotection in females. However, no information exists regarding effect of testosterone on PI3K/Akt pathway following I/R. We hypothesize that:
endogenous or exogenous testosterone will decrease cardiac PI3K/Akt activation during I/R;
Adding testosterone to cardiomyocyte in vitro may reduce PI3K/Akt activation and aggravate cell damage under hypoxia.
Methods: Rat hearts of age-matched adult male, female, castrated male, male with 3-week flutamide treatment, castrated male with 3-week 5α-dihydrotestosterone (DHT) implantation or acute (5-min) testosterone infusion (ATI) were subjected to I/R (Langendorff). Rat cardiomyocytes (H9c2) were cultured with 0, 10, 100 and 1000 nM of testosterone under normoxia or 1% O2 (hypoxia) for 4 hours. Supernatants were collected for LDH assay (ELISA). Heart tissue and cell lysates were assessed for activation of Akt/PI3K (Western Blot). Data were analyzed with student’s t-test.
Results: Myocardial Akt/PI3K activation after I/R, and LDH release in rat cardiomyocytes under hypoxia are shown in tables⇓⇓. Under normoxia, testosterone did not affect Akt/PI3K activation and LDH release.
Conclusion: Our study represents the first evidence of testosterone-mediated Akt/PI3K down-regulation in male hearts following I/R, indicating a possible mechanism underlying increased myocardial injury by testosterone after I/R.