Objective: We recently reported decreased σ 1 receptor expression in the heart after abdominal aortic stenosis in bilateral ovariectomized rats. Here, we use ovariectomized female rats to investigate the distinct cardioprotective effects of 17β-estradiol (E 2) and dehydroepiandrosterone (DHEA) in pressure overload (PO)-induced cardiac dysfunction. Methods: E 2 (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. Results: Both E 2 and DHEA treatments significantly inhibited PO-induced increases both in heart weight/body weight ratio and lung weight/body weight ratios. Both E 2 and DHEA also ameliorated hypertrophy-induced impairment of left ventricular end-diastolic pressure, left ventricular-developed pressure, left ventricular contraction and relaxation (±dp/dt) rates, heart rate, and mean arterial blood pressure. Notably, DHEA but not E 2 administration rescued decreased PO-induced σ 1 receptor reduction in the heart. Coadministration with N,N-Dipropyl-2-[4-methoxy-3-(2-phenylethoxy) phenyl]-ethylamine monohydrochloride, an σ1 receptor antagonist, inhibited DHEA-induced amelioration of heart dysfunction without altering E 2-induced cardioprotection. Mechanistically, both E 2 and DHEA treatments significantly restored PO-induced decreases in protein kinase B (Akt) phosphorylation and Akt-mediated endothelial nitric oxide synthase (eNOS) phosphorylation (Ser1179). N,N-Dipropyl-2-[4-methoxy-3-(2-phenylethoxy) phenyl]-ethylamine monohydrochloride treatment totally abolished DHEA-induced Akt and eNOS phosphorylation without altering E 2-induced Akt-eNOS activation. Conclusions: Taken together, these results from an ovariectomized rat model of PO-induced cardiac dysfunction show that DHEA but not E 2 elicits a cardioprotective action through σ 1 receptor activation. DHEA-induced Akt-eNOS activation through σ 1 receptors is probably associated with its cardioprotective activity.
ASJC Scopus subject areas
- Obstetrics and Gynaecology