Stimulation of Sigma-1 receptor signaling by dehydroepiandrosterone ameliorates pressure overload-induced hypertrophy and dysfunctions in ovariectomized rats

Md Shenuarin Bhuiyan, Kohji Fukunaga

Research output: Contribution to journalArticle

25 Citations (Scopus)

Abstract

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/dtmax). DHEA treatment significantly restored PO-induced impaired eNOS and Akt activity in the LV. Conclusion: 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.

Original languageEnglish
Pages (from-to)1253-1265
Number of pages13
JournalExpert Opinion on Therapeutic Targets
Volume13
Issue number11
DOIs
Publication statusPublished - 2009 Nov 1

Keywords

  • Sigma-1 receptor (Sig-1R)
  • dehydroepiandrosterone (DHEA)
  • endothelial nitric oxide synthase (eNOS)
  • myocardial hypertrophy
  • ovariectomy
  • protein kinase B (Akt)

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology
  • Drug Discovery
  • Clinical Biochemistry

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