Fluvoxamine rescues mitochondrial Ca2 + transport and ATP production through σ1-receptor in hypertrophic cardiomyocytes

Hideaki Tagashira, Md Shenuarin Bhuiyan, Norifumi Shioda, Kohji Fukunaga

Research output: Contribution to journalArticlepeer-review

33 Citations (Scopus)

Abstract

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 Ca2 + transport, little is known about its physiological and pathological relevance in cardiomyocytes. Main methods Here we performed Ca2 + imaging and measured ATP production to define the role of σ1Rs in regulating sarcoplasmic reticulum (SR)-mitochondrial Ca2 + 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 Ca2 + mobilization from the SR and ATP production. Interestingly, σ1R stimulation with fluvoxamine rescued impaired mitochondrial Ca2 + 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 Ca2 + 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 Ca2 + transport and mitochondrial ATP production, whereas σ1R stimulation suppresses intracellular Ca2 + overload through IP3Rs and RyRs. These mechanisms likely underlie in part the anti-hypertrophic and cardioprotective action of the σ1R agonists including fluvoxamine.

Original languageEnglish
Pages (from-to)89-100
Number of pages12
JournalLife Sciences
Volume95
Issue number2
DOIs
Publication statusPublished - 2014 Jan 30

Keywords

  • ATP
  • Fluvoxamine
  • Mitochondrial Ca transport
  • Myocardial hypertrophy
  • σ receptor

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Pharmacology, Toxicology and Pharmaceutics(all)

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