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Am J Physiol Heart Circ Physiol. 2010 Nov;299(5):H1535-45. doi: 10.1152/ajpheart.00198.2010. Epub 2010 Aug 27.

Sigma1-receptor stimulation with fluvoxamine ameliorates transverse aortic constriction-induced myocardial hypertrophy and dysfunction in mice.

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  • 1Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan.

Abstract

Selective serotonin reuptake inhibitors (SSRIs) are known to reduce post-myocardial infarction-induced morbidity and mortality. However, the molecular mechanism underlying SSRI-induced cardioprotection remains unclear. Here, we investigated the role of σ(1)-receptor (σ(1)R) stimulation with fluvoxamine on myocardial hypertrophy and cardiac functional recovery. Male ICR mice were subjected to transverse aortic constriction (TAC) in the cardiac aortic arch. To confirm the cardioprotective role of fluvoxamine by σ(1)R stimulation, we treated mice with fluvoxamine (0.5 or 1 mg/kg) orally once per day for 4 wk after the onset of aortic banding. Interestingly, in untreated mice, σ(1)R expression in the left ventricle (LV) decreased significantly over the 4 wk as TAC-induced hypertrophy increased. In contrast, fluvoxamine administration significantly attenuated TAC-induced myocardial hypertrophy concomitant with recovery of σ(1)R expression in the LV. Fluvoxamine also attenuated hypertrophy-induced impaired LV fractional shortening. The fluvoxamine cardioprotective effect was nullified by treatment with a σ(1)R antagonist [NE-100 (1 mg/kg)]. Importantly, another SSRI with very low affinity for σ(1)Rs, paroxetine, did not elicit antihypertrophic effects in TAC mice and cultured cardiomyocytes. Fluvoxamine treatment significantly restored TAC-induced impaired Akt and endothelial nitric oxide synthase (eNOS) phosphorylation in the LV. Our findings suggest that fluvoxamine protects against TAC-induced cardiac dysfunction via upregulated σ(1)R expression and stimulation of σ(1)R-mediated Akt-eNOS signaling in mice. This is the first report of a potential role for σ(1)R stimulation by fluvoxamine in attenuating cardiac hypertrophy and restoring contractility in TAC mice.

PMID:
20802134
[PubMed - indexed for MEDLINE]
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