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

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.

Crucial Interactions Between Selective Serotonin Uptake Inhibitors and Sigma-1 Receptor in Heart Failure

“…Along with progression of LV hypertrophy, sigma-1 receptor expression was significantly reduced in the LV of ovariectomized rats ( Fig. 2A) (20) and showed a significant negative linear correlation with heart function in mice with transverse aortic constriction (TAC) (22). We also confirmed decreased expression of sigma-1 receptor in LV following cardiac hypertrophy and failure by an immunohistochemical study (19).…”

“…Our results showing sigma-1 receptor upregulation by fluvoxamine reveal complexity (22). Although fluvoxamine-induced Akt and eNOS phosphorylation was completely abolished by pre-administration of the sigma-1 receptor antagonist NE-100, the fluvoxamine-induced sigma-1 receptor upregulation was not inhibited by NE-100 (Fig.…”

“…One study from another laboratory showed that fluvoxamine administration at a dose used in our experiments (22) attenuated sympathetic hyperactivation and improved depression-like behavior (23). Although these mechanisms remain unclear, our work suggests that the cardiac sigma-1 receptor and its downstream signaling protect the heart against TAC (22) and PO-induced cardiomyopathy (21,25).…”

“…Although these mechanisms remain unclear, our work suggests that the cardiac sigma-1 receptor and its downstream signaling protect the heart against TAC (22) and PO-induced cardiomyopathy (21,25). Previously, we also reported in several studies that the neurosteroid dehydroepiandrosterone (DHEA) serves as an endogenous ligand for the sigma-1 receptor and that treatment with DHEA ameliorated PO-induced cardiac injury by up-regulating the cardiac sigma-1 receptor in heart and activating downstream signaling (21,26,27).…”

Blockade of sigma 1 receptors alleviates sensory signs of diabetic neuropathy in rats

“…Accordingly, the electrophysiological response of Aδ‐fibres to mechanical stimulation was evaluated using the skin–saphenous nerve preparation (Reeh, 1986; Kress et al, 1992). Finally, as reduced nerve perfusion is an important factor in the aetiology of diabetic neuropathy (Cameron and Cotter, 1997) and decreased nerve blood flow and hypoxia in neuropathic diabetes patients have been related to the neurovascular dysfunction (Cameron and Cotter, 1992, 1994), the vascular reactivity of conduit (aorta) and resistance (mesenteric) vessels have been evaluated (Tagashira et al., 2010; Amer et al., 2013) as a first approach.…”