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Cardioprotective effect of fluvoxamine, sigma-1 receptor high affinity agonist.
MedLine Citation:
PMID:  22293694     Owner:  NLM     Status:  In-Data-Review    
Abstract/OtherAbstract:
Selective serotonin reuptake inhibitors (SSRIs) are known to reduce post-myocardial infarction (MI)-induced morbidity and mortality. However, the molecular mechanism underlying SSRI-induced cardioprotection remains unclear. Here, we investigated the role of sigma-1 receptor (Sig-1R) stimulation with fluvoxamine on myocardial hypertrophy and cardioprotection. Male ICR mice were subjected to transverse aortic constriction (TAC) in the cardiac aortic arch. To confirm the cardioprotective role of Sig-1R stimulation by fluvoxamine, we treated mice with fluvoxamine (0.5 or 1 mg/kg) orally once a day for 4 weeks after onset of aortic banding. Interestingly, in untreated mice, Sig-1R expression in the left ventricle (LV) markedly decreased over 4 weeks with increased hypertrophy. By contrast, fluvoxamine administration significantly attenuated TAC-induced myocardial hypertrophy concomitant with recovery of Sig-1R expression in LV. Fluvoxamine also attenuated hypertrophy-induced impaired LV fractional shortening. The fluvoxamine cardioprotective effect was nullified by treatment with a Sig-1R antagonist, NE-100 (1 mg/kg). Importantly, another SSRI with very low affinity for Sig-1R, paroxetine, did not exhibit antihypertrophic effects in TAC mice and in cultured cardiomyocyte treated with angiotensin II. Fluvoxamine treatment significantly restored TAC-induced impaired Akt and eNOS phosphorylation in LV. Our findings suggest that fluvoxamine protects heart against TAC-induced cardiac dysfunction via upregulation of Sig-1R and stimulation of Sig-1R-mediated Akt-eNOS signaling in mice. This is the first report of a potential role of Sig-1R stimulation by fluvoxamine in preventing cardiac hypertrophy and myocardial injury in TAC mice.
Authors:
Hideaki Tagashira; Kohji Fukunaga
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Publication Detail:
Type:  Journal Article    
Journal Detail:
Title:  Yakugaku zasshi : Journal of the Pharmaceutical Society of Japan     Volume:  132     ISSN:  1347-5231     ISO Abbreviation:  Yakugaku Zasshi     Publication Date:  2012  
Date Detail:
Created Date:  2012-02-01     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  0413613     Medline TA:  Yakugaku Zasshi     Country:  Japan    
Other Details:
Languages:  eng     Pagination:  167-72     Citation Subset:  IM    
Affiliation:
Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Tohoku University.
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