fluvoxamine and Hypertrophy--Left-Ventricular

We here investigated the effect of sigma-1 receptor (Sig-1R) stimulation with fluvoxamine on myocardial hypertrophy, cardiac functional recovery and defined mechanisms underlying its cardioprotective action.. Wistar rats subjected to bilateral ovariectomy (OVX) were treated with abdominal aortic banding between the right and left renal arteries. To confirm the cardioprotective role of Sig-1R stimulation, we treated the rats with Sig-1R agonist (fluvoxamine, 0.5 and 1 mg/kg) orally once a day for 4 weeks after the onset of aortic banding.. Interestingly, the expression of Sig-1R in the left ventricle (LV) decreased significantly 4 weeks after pressure overload (PO)-induced hypertrophy in OVX rats. The fluvoxamine administration significantly attenuated PO-induced myocardial hypertrophy with concomitant increase in the expression of Sig-1R in LV. Fluvoxamine also attenuated hypertrophy-induced impaired LV functions. The cardioprotective effect of fluvoxamine was nullified by treatment with Sig-1R antagonist (NE-100; 1 mg/kg). Fluvoxamine treatment significantly restored PO-induced impaired eNOS and Akt activity in the LV.. We here found, for the first time, the potential role of Sig-1R expression in the heart in attenuating PO-induced hypertrophy in OVX rats. Fluvoxamine treatment protects PO-induced cardiac injury via upregulation of Sig-1R and stimulation of Sig-1R-mediated Akt-eNOS signaling in ovariectomized rats.

Topics: Animals; Anisoles; Blood Pressure; Cardiotonic Agents; Female; Fluvoxamine; Heart; Humans; Hypertrophy, Left Ventricular; Myocardium; Ovariectomy; Propylamines; Rats; Rats, Wistar; Receptors, Glycine; Receptors, sigma; Selective Serotonin Reuptake Inhibitors; Sigma-1 Receptor; Signal Transduction; Up-Regulation

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.

Topics: Animals; Aorta; Cells, Cultured; Fluvoxamine; Hypertrophy, Left Ventricular; Male; Mice; Mice, Inbred ICR; Models, Animal; Myocardial Contraction; Myocytes, Cardiac; Nitric Oxide Synthase Type III; Paroxetine; Phosphorylation; Proto-Oncogene Proteins c-akt; Rats; Rats, Wistar; Receptors, sigma; Selective Serotonin Reuptake Inhibitors; Sigma-1 Receptor; Time Factors; Vasoconstriction; Ventricular Dysfunction, Left