Fluvoxamine rescues mitochondrial Ca2+ transport and ATP production through σ(1)-receptor in hypertrophic cardiomyocytes.

AIMS

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.

MAIN METHODS

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.

KEY FINDING

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.

SIGNIFICANCE

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.