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


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.


CONCLUSIONS
Taken together chronic beta-adrenergic stimulation caused severe cardiac injury in OVX rats through calpain activation and impairments of Akt and eNOS signaling pathways.
Bhuiyan
Md Shenuarin
MS
Department of Pharmacology, Tohoku University, Aramaki-Aoba Aoba-ku, Sendai 980 8578, Japan.
Shioda
Norifumi
N
Fukunaga
Kohji
K
D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002135:Calcium-Binding Proteins / Q000378:metabolism; D002154:Calpain / Q000037:antagonists & inhibitors / Q000378:metabolism*; D005260:Female; D006352:Heart Ventricles / Q000503:physiopathology; D007545:Isoproterenol / Q000494:pharmacology; D052250:Nitric Oxide Synthase Type III / Q000187:drug effects / Q000378:metabolism*; D010052:Ovariectomy; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D011943:Receptors, Adrenergic, beta / Q000187:drug effects / Q000378:metabolism*; D015398:Signal Transduction
D000318:Adrenergic beta-Agonists; D002135:Calcium-Binding Proteins; D011943:Receptors, Adrenergic, beta; C033668:calpastatin; D052250:Nitric Oxide Synthase Type III; D051057:Proto-Oncogene Proteins c-akt; D002154:Calpain; D007545:Isoproterenol; D002118:Calcium