fluvoxamine and Cardiomegaly

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.

Topics: Animals; Cardiomegaly; Cardiotonic Agents; Disease Models, Animal; Fluvoxamine; Heart Ventricles; Male; Mice; Mice, Inbred ICR; Nitric Oxide Synthase Type III; Paroxetine; Proto-Oncogene Proteins c-akt; Receptors, sigma; Selective Serotonin Reuptake Inhibitors; Sigma-1 Receptor; Signal Transduction

We previously reported that fluvoxamine, a selective serotonin reuptake inhibitor with high affinity for the σ1-receptor (σ1R), ameliorates cardiac hypertrophy and dysfunction via σ1R stimulation. Although σ1R on non-cardiomyocytes interacts with the IP3 receptor (IP3R) to promote mitochondrial Ca(2+) transport, little is known about its physiological and pathological relevance in cardiomyocytes.. Here we performed Ca(2+) imaging and measured ATP production to define the role of σ1Rs in regulating sarcoplasmic reticulum (SR)-mitochondrial Ca(2+) transport in neonatal rat ventricular cardiomyocytes treated with angiotensin II to promote hypertrophy.. These cardiomyocytes exhibited imbalances in expression levels of σ1R and IP3R and impairments in both phenylephrine-induced mitochondrial Ca(2+) mobilization from the SR and ATP production. Interestingly, σ1R stimulation with fluvoxamine rescued impaired mitochondrial Ca(2+) mobilization and ATP production, an effect abolished by treatment of cells with the σ1R antagonist, NE-100. Under physiological conditions, fluvoxamine stimulation of σ1Rs suppressed intracellular Ca(2+) mobilization through IP3Rs and ryanodine receptors (RyRs). In vivo, chronic administration of fluvoxamine to TAC mice also rescued impaired ATP production.. These results suggest that σ1R stimulation with fluvoxamine promotes SR-mitochondrial Ca(2+) transport and mitochondrial ATP production, whereas σ1R stimulation suppresses intracellular Ca(2+) overload through IP3Rs and RyRs. These mechanisms likely underlie in part the anti-hypertrophic and cardioprotective action of the σ1R agonists including fluvoxamine.

Topics: Adenosine Triphosphate; Angiotensin II; Animals; Calcium; Cardiomegaly; Cells, Cultured; Fluvoxamine; Immunohistochemistry; Male; Mice; Mitochondria; Myocytes, Cardiac; Rats; Receptors, sigma; Selective Serotonin Reuptake Inhibitors

In the present study, we investigated the vasculoprotective effect of sigma-1 receptor stimulation with fluvoxamine on pressure overload hypertrophy-induced vascular injury in the thoracic aorta and defined mechanisms underlying that activity. Wistar rats underwent bilateral ovariectomy, and two weeks later were further treated with abdominal aortic stenosis. To confirm the vasculoprotective role of sigma-1 receptor signaling, we treated rats with the agonist fluvoxamine (at 0.5 and 1.0 mg/kg) and with the antagonist NE-100 (at 1.0mg/kg) for 4 weeks orally once a day after the onset of aortic banding. Interestingly, sigma-1 receptor expression in the thoracic aorta decreased significantly 4 weeks after pressure overload-induced hypertrophy in vehicle treated ovariectomized rats. Fluvoxamine administration significantly attenuated pressure overload-induced vascular injury with concomitant increase in receptor expression and subsequent decrease in IP3 receptor expression. Fluvoxamine treatment also significantly restored pressure overload-induced impaired Akt phosphorylation and stimulated eNOS protein expression as well as Akt-mediated eNOS phosphorylation (Ser1177). Fluvoxamine's vasculoprotective effect was nullified by co-administration of a sigma-1 receptor antagonist. No changes in phosphorylation of ERK1/2 or PKCα in the aorta were observed following pressure overload and after fluvoxamine treatment. Our findings confirm, for the first time, a potential role for sigma-1 receptor expression and signaling in the thoracic aorta in attenuating hypertrophy-induced vascular injury in ovariectomized rats. Thus, we demonstrate, for the first time, a potential role in the thoracic aorta for sigma-1 receptor expression and signaling via Akt-eNOS in attenuating hypertrophy-induced vascular injury in ovariectomized rats.

Topics: Animals; Anisoles; Aorta, Abdominal; Aorta, Thoracic; Aortic Valve Stenosis; Cardiomegaly; Dose-Response Relationship, Drug; Female; Fluvoxamine; Nitric Oxide Synthase Type III; Ovariectomy; Phosphorylation; Propylamines; Proto-Oncogene Proteins c-akt; Rats; Rats, Wistar; Receptors, sigma; Selective Serotonin Reuptake Inhibitors; Sigma-1 Receptor; Signal Transduction