Stimulation of σ1-receptor restores abnormal mitochondrial Ca2 + mobilization and ATP production following cardiac hypertrophy

Hideaki Tagashira, Chen Zhang, Ying Mei Lu, Hideyuki Hasegawa, Hiroshi Kanai, Feng Han, Kohji Fukunaga

Research output: Contribution to journalArticlepeer-review

31 Citations (Scopus)

Abstract

Background We previously reported that the σ1-receptor (σ1R) is down-regulated following cardiac hypertrophy and dysfunction in transverse aortic constriction (TAC) mice. Here we address how σ1R stimulation with the selective σ1R agonist SA4503 restores hypertrophy-induced cardiac dysfunction through σ1R localized in the sarcoplasmic reticulum (SR). Methods We first confirmed anti-hypertrophic effects of SA4503 (0.1-1 μM) in cultured cardiomyocytes exposed to angiotensin II (Ang II). Then, to confirm the ameliorative effects of σ1R stimulation in vivo, we administered SA4503 (1.0 mg/kg) and the σ1R antagonist NE-100 (1.0 mg/kg) orally to TAC mice for 4 weeks (once daily). Results σ1R stimulation with SA4503 significantly inhibited Ang II-induced cardiomyocyte hypertrophy. Ang II exposure for 72 h impaired phenylephrine (PE)-induced Ca2 + mobilization from the SR into both the cytosol and mitochondria. Treatment of cardiomyocytes with SA4503 largely restored PE-induced Ca2 + mobilization into mitochondria. Exposure of cardiomyocytes to Ang II for 72 h decreased basal ATP content and PE-induced ATP production concomitant with reduced mitochondrial size, while SA4503 treatment completely restored ATP production and mitochondrial size. Pretreatment with NE-100 or siRNA abolished these effects. Chronic SA4503 administration also significantly attenuated myocardial hypertrophy and restored ATP production in TAC mice. SA4503 administration also decreased hypertrophy-induced impairments in LV contractile function. Conclusions σ1R stimulation with the specific agonist SA4503 ameliorates cardiac hypertrophy and dysfunction by restoring both mitochondrial Ca 2 + mobilization and ATP production via σ1R stimulation. General significance Our observations suggest that σ1R stimulation represents a new therapeutic strategy to rescue the heart from hypertrophic dysfunction.

Original languageEnglish
Pages (from-to)3082-3094
Number of pages13
JournalBiochimica et Biophysica Acta - General Subjects
Volume1830
Issue number4
DOIs
Publication statusPublished - 2013 Apr

Keywords

  • ATP
  • ATP production
  • Calcium signaling
  • Mitochondria
  • Sigma receptor

ASJC Scopus subject areas

  • Biophysics
  • Biochemistry
  • Molecular Biology

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