Abstract P229: Nongenomic Cardioprotective Effect of Dehydroepiandrosterone on Cardiac Hypertrophy: Comparison with 17β-Estradiol-Induced Cardioprotection
Objective: We recently reported a decreased σ1 receptor expression in heart following abdominal aortic stenosis in bilateral ovariectomized (OVX) rats. Here, we demonstrated non-genemic cardioprotective effects of dehydroepiandrosterone (DHEA) though σ1 receptor in pressure overload (PO)-induced cardiac dysfunction.
Methods: Bilateral ovariectomy was performed in female rats. Two weeks after the sham operation or ovariectomy, pressure-overload was initiated by abdominal aortic banding. 17β-estradiol (E2: 0.1 mg/kg) and DHEA (30 mg/kg) were administered to rats subcutaneously and orally, respectively, for 14 days starting 2 weeks after aortic banding. Hemodynamic parameters and cardiac hypertrophy were measured after 2 weeks of drug treatment. After dissection out of left ventricular, gene expression and hypertrophic signaling were analyzed by real-time RT-PCR and western blot, respectively.
Results: Both E2 and DHEA treatments significantly inhibited pressure overload-induced increases both in heart weight/body weight (HW/BW) ratio and lung weight/body weight (LW/BW) ratios. Both E2 and DHEA treatments also ameliorated hypertrophy-induced impairment of left ventricular end diastolic pressure (LVEDP), left ventricular developed pressure (LVDP), left ventricular contraction and relaxation (±dp/dt) rates, heart rate (HR) and mean arterial blood pressure (MABP). Notably, DHEA but not E2 administration rescued PO-induced σ1 receptor downregulation in left ventricular. Co-administration with NE-100, a σ1 receptor selective antagonist, inhibited DHEA-induced amelioration of heart dysfunction without effects on E2-induced cardioprotection. Mechanistically, both E2 and DHEA treatments significantly restored PO-induced decreases in Akt phosphorylation and Akt-mediated eNOS phosphorylation (Ser1179). NE-100 treatment totally abolished DHEA-induced Akt and eNOS phosphorylation without effects on E2-induced Akt/eNOS activation.
Conclusions: Taken together, based on these results with OVX rat heart, DHEA but not E2 elicits cardioprotective action through σ1 receptor activation. DHEA-induced Akt/eNOS activation through σ1 receptors likely mediates the cardioprotective activity.
- © 2011 by American Heart Association, Inc.