1-Receptor stimulation with fluvoxamine ameliorates transverse aortic constriction-induced myocardial hypertrophy and dysfunction in mice

Tagashira H, Bhuiyan S, Shioda N, Hasegawa H, Kanai H, Fukunaga K. 1-Receptor stimulation with fluvoxamine ameliorates transverse aortic constriction-induced myocardial hypertrophy and dysfunction in mice. Am J Physiol Heart Circ Physiol 299: H1535–H1545, 2010. First published August 27, 2010; doi:10.1152/ajpheart.00198.2010.—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 1-receptor ( 1R) 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 1R 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, 1R expression in the left ventricle (LV) decreased significantly over the 4 wk as TACinduced hypertrophy increased. In contrast, fluvoxamine administration significantly attenuated TAC-induced myocardial hypertrophy concomitant with recovery of 1R expression in the LV. Fluvoxamine also attenuated hypertrophy-induced impaired LV fractional shortening. The fluvoxamine cardioprotective effect was nullified by treatment with a 1R antagonist [NE-100 (1 mg/kg)]. Importantly, another SSRI with very low affinity for 1Rs, 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 TACinduced cardiac dysfunction via upregulated 1R expression and stimulation of 1R-mediated Akt-eNOS signaling in mice. This is the first report of a potential role for 1R stimulation by fluvoxamine in attenuating cardiac hypertrophy and restoring contractility in TAC mice.