alexa Chronic beta-AR activation-induced calpain activation and impaired eNOS-Akt signaling mediates cardiac injury in ovariectomized female rats.
Genetics & Molecular Biology

Genetics & Molecular Biology

Journal of Molecular and Genetic Medicine

Author(s): Bhuiyan MS, Shioda N, Fukunaga K

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Abstract OBJECTIVE: To address the pathophysiological relevance of ovarian hormones in chronic beta-adrenergic stimulation-induced myocardial injury, we assessed impairments of Ca(2+)-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 beta-adrenergic agonist, once a day for 28 days. RESULTS: We found that chronic beta-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 beta-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 3beta phosphorylation underlying cell injury following chronic beta-adrenergic stimulation. CONCLUSION: Taken together chronic beta-adrenergic stimulation caused severe cardiac injury in OVX rats through calpain activation and impairments of Akt and eNOS signaling pathways. This article was published in Expert Opin Ther Targets and referenced in Journal of Molecular and Genetic Medicine

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