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


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.


CONCLUSIONS
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.
Bhuiyan
Md Shenuarin
MS
Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan.
Tagashira
Hideaki
H
Fukunaga
Kohji
K
D000818:Animals; D001013:Aorta, Thoracic / Q000378:metabolism*; D003687:Dehydroepiandrosterone / Q000494:pharmacology* / Q000627:therapeutic use; D005260:Female; D017379:Hypertrophy, Left Ventricular / Q000378:metabolism*; D052250:Nitric Oxide Synthase Type III / Q000502:physiology*; D010052:Ovariectomy; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology*; D051381:Rats; D017208:Rats, Wistar; D017480:Receptors, sigma / Q000187:drug effects / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D000097605:Sigma-1 Receptor
D003687:Dehydroepiandrosterone; D052250:Nitric Oxide Synthase Type III; D051057:Proto-Oncogene Proteins c-akt; D017480:Receptors, sigma; D000097605:Sigma-1 Receptor