Dehydroepiandrosterone-mediated stimulation of sigma-1 receptor activates Akt-eNOS signaling in the thoracic aorta of ovariectomized rats with abdominal aortic banding.

Abstract

OBJECTIVE:

Decreased dehydroepiandrosterone (DHEA) levels are associated with endothelial dysfunction and increased cardiovascular mortality in postmenopausal women. Using ovariectomized rats, we first defined whether expression of sigma-1 receptor (Sig-1R) in the aorta is regulated following pressure overload (PO) and also after DHEA treatment. We also investigated effects of DHEA known as Sig-1R agonist on impaired Akt/endothelial nitric oxide synthase (eNOS) signaling in the thoracic aorta under PO.

RESEARCH DESIGN/METHODS:

Wistar rats subjected to bilateral ovariectomy (OVX) were further treated with abdominal aortic stenosis 2 weeks later. DHEA (15 and 30 mg/kg) was administered orally once a day for 14 days starting from 2 weeks after the aortic banding.

RESULTS:

Time course study indicated that expression of Sig-1R expression and eNOS decreased time dependently in the thoracic aorta from 1 to 4 weeks after PO. DHEA treatment significantly inhibited the decreased Sig-1R expression in the thoracic aorta. The DHEA treatment also significantly restored PO-induced impaired Akt phosphorylation and stimulated eNOS protein expression with concomitant increased Akt-mediated eNOS phosphorylation (Ser1177). We did not find any changes in the phosphorylation of ERK1/2 and PKCα in the aorta following PO and after treatment with DHEA.

CONCLUSION:

We here reported, for the first time, that DHEA treatment induces the upregulation and stimulation of Sig-1R in the thoracic aorta that stimulate Sig-1R-mediated Akt-eNOS signaling pathways in ovariectomized rats under PO.

• Authors: Md Shenuarin Bhuiyan, Hideaki Tagashira, Kohji Fukunaga
• Journal: Cardiovascular therapeutics (Cardiovasc Ther) Vol. 29 Issue 4 Pg. 219-30 (Aug 2011) ISSN: 1755-5922 [Electronic] England
• PMID: 20553277 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2010 Blackwell Publishing Ltd.

Chemical References

• Receptors, sigma
• Dehydroepiandrosterone
• Nitric Oxide Synthase Type III
• Proto-Oncogene Proteins c-akt

Topics

• Animals
• Aorta, Thoracic (metabolism)
• Dehydroepiandrosterone (pharmacology, therapeutic use)
• Female
• Hypertrophy, Left Ventricular (metabolism)
• Nitric Oxide Synthase Type III (physiology)
• Ovariectomy
• Proto-Oncogene Proteins c-akt (physiology)
• Rats
• Rats, Wistar
• Receptors, sigma (drug effects, physiology)
• Signal Transduction (physiology)
• Sigma-1 Receptor