title: [Cardioprotective effect of fluvoxamine, sigma-1 receptor high affinity agonist].
abstract: 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.affiliation: Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan.
authors.forename: Hideaki
authors.initials: H
authors.lastname: Tagashira
authors.forename: Kohji
authors.initials: K
authors.lastname: Fukunaga
mesh_terms: D000818:Animals; D006332:Cardiomegaly / Q000188:drug therapy / Q000473:pathology / Q000517:prevention & control; D002316:Cardiotonic Agents; D004195:Disease Models, Animal; D016666:Fluvoxamine / Q000494:pharmacology* / Q000627:therapeutic use; D006352:Heart Ventricles / Q000378:metabolism; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D052250:Nitric Oxide Synthase Type III / Q000502:physiology; D017374:Paroxetine / Q000494:pharmacology / Q000627:therapeutic use; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology; D017480:Receptors, sigma / Q000819:agonists* / Q000378:metabolism; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D015398:Signal Transduction / Q000502:physiology; D000097605:Sigma-1 Receptor
chemical_list: D002316:Cardiotonic Agents; D016666:Fluvoxamine; D052250:Nitric Oxide Synthase Type III; D017374:Paroxetine; D051057:Proto-Oncogene Proteins c-akt; D017480:Receptors, sigma; D017367:Selective Serotonin Reuptake Inhibitors; D000097605:Sigma-1 Receptor