σ1-receptor stimulation with fluvoxamine ameliorates transverse aortic constriction-induced myocardial hypertrophy and dysfunction in mice

Hideaki Tagashira, Shenuarin Bhuiyan, Norifumi Shioda, Hideyuki Hasegawa, Hiroshi Kanai, Kohji Fukunaga

Research output: Contribution to journalArticle

36 Citations (Scopus)

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 σ1-receptor (σ1R) 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 σ1R 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, σ1R 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 σ1R expression in the LV. Fluvoxamine also attenuated hypertrophy-induced impaired LV fractional shortening. The fluvoxamine cardioprotective effect was nullified by treatment with a σ1R antagonist [NE-100 (1 mg/kg)]. Importantly, another SSRI with very low affinity for σ1Rs, 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 σ1R expression and stimulation of σ1R-mediated Akt-eNOS signaling in mice. This is the first report of a potential role for σ1R stimulation by fluvoxamine in attenuating cardiac hypertrophy and restoring contractility in TAC mice.

Original languageEnglish
Pages (from-to)H1535-H1545
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume299
Issue number5
DOIs
Publication statusPublished - 2010 Nov 1

Keywords

  • Akt
  • Endothelial nitric oxide synthase
  • Protein kinase B

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

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