Chronic β-AR activation-induced calpain activation and impaired eNOS-Akt signaling mediates cardiac injury in ovariectomized female rats

Md Shenuarin Bhuiyan, Norifumi Shioda, Kohji Fukunaga

Research output: Contribution to journalArticle

14 Citations (Scopus)

Abstract

Objective: To address the pathophysiological relevance of ovarian hormones in chronic β-adrenergic stimulation-induced myocardial injury, we assessed impairments of Ca2+-mediated cell signaling in the left ventricle of ovariectomized female rats. Research design/methods: Female Wistar rats were subjected to bilateral ovariectomy and sham operation. Six weeks after ovariectomy (OVX), both OVX and sham rats were treated with isoproterenol (5mg/kg, intraperitoneally), a nonselective β-adrenergic agonist, once a day for 28 days. Results: We found that chronic β-adrenergic stimulation caused enhanced breakdown of sarcolemmal proteins such as dystrophin and utrophin in OVX rats compared to sham-operated rats. Generation of calpain-mediated 150 kDa-breakdown product of spectrin confirmed calpain activation following isoproterenol treatment. Marked breakdown of endogenous calpain inhibitor, calpastatin, in OVX rats was consistent with the calpain activation following chronic β-adrenergic stimulation. In addition to calpain activation, we also found marked reduction of endothelial nitric oxide synthase (eNOS) activity with concomitant deregulation by heat shock proteins 90 kDa and caveolin 3, both of which are eNOS-associated proteins. Finally, we documented decreased Akt phosphorylation with concomitant increased glycogen synthase kinase 3β phosphorylation underlying cell injury following chronic β-adrenergic stimulation. Conclusion: Taken together chronic β-adrenergic stimulation caused severe cardiac injury in OVX rats through calpain activation and impairments of Akt and eNOS signaling pathways.

Original languageEnglish
Pages (from-to)275-286
Number of pages12
JournalExpert Opinion on Therapeutic Targets
Volume13
Issue number3
DOIs
Publication statusPublished - 2009 Mar 1

Keywords

  • Akt
  • Calpain
  • Isoproterenol
  • Ovariectomy
  • eNOS

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology
  • Drug Discovery
  • Clinical Biochemistry

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