Stimulation of sigma-1 receptor signaling by dehydroepiandrosterone ameliorates pressure overload-induced hypertrophy and dysfunctions in ovariectomized rats.
OBJECTIVE
Decreased dehydroepiandrosterone (DHEA) levels are associated with endothelial dysfunction and increased cardiovascular mortality in postmenopausal women. We investigated the role of DHEA, also known as sigma-1 receptor (Sig-1R) agonist, in myocardial hypertrophy, cardiac functional recovery and defined mechanisms of cardioprotective action.


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


RESULTS
Time course study indicated that left ventricle (LV) weight:body weight (BW) ratio increased time-dependently from 1 to 4 weeks after pressure-overload (PO) with significant inversed regulation of Sig-1R expression. Treatment with the Sig-1R agonist, DHEA, significantly attenuated PO-induced myocardial hypertrophy with increased expression of Sig-1R in the LV. DHEA also attenuated hypertrophy-induced impaired LV end diastolic pressure, LV developed pressure and LV contractility (+/- dp/dt(max)). DHEA treatment significantly restored PO-induced impaired eNOS and Akt activity in the LV.


CONCLUSIONS
We report, for the first time to our knowledge, the potential role of Sig-1R expression in the heart to attenuate PO-induced hypertrophy in ovariectomized rats. DHEA treatment protects against PO-induced cardiac injury via upregulation of Sig-1R and stimulation of Sig-1R-mediated Akt-eNOS signaling.
Bhuiyan
Md Shenuarin
MS
Tohoku University, Graduate School of Pharmaceutical Sciences, Department of Pharmacology, Aramaki-Aoba, Aoba-ku, Sendai 980-8578, Japan.
Fukunaga
Kohji
K
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002316:Cardiotonic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D003687:Dehydroepiandrosterone / Q000008:administration & dosage / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005260:Female; D017379:Hypertrophy, Left Ventricular / Q000517:prevention & control*; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D010052:Ovariectomy; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D017480:Receptors, sigma / Q000819:agonists* / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D015854:Up-Regulation / Q000187:drug effects; D000097605:Sigma-1 Receptor
D002316:Cardiotonic Agents; D003687:Dehydroepiandrosterone; D052250:Nitric Oxide Synthase Type III; D051057:Proto-Oncogene Proteins c-akt; D017480:Receptors, sigma; D000097605:Sigma-1 Receptor