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

AbstractBACKGROUND:
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 (0.1-1μM) in cultured cardiomyocytes exposed to angiotensin II (Ang II). Then, to confirm the ameliorative effects of σ1R stimulation in vivo, we administered SA4503 (1.0mg/kg) and the σ1R antagonist NE-100 (1.0mg/kg) orally to TAC mice for 4weeks (once daily).
RESULTS:
σ1R stimulation with SA4503 significantly inhibited Ang II-induced cardiomyocyte hypertrophy. Ang II exposure for 72h impaired phenylephrine (PE)-induced Ca(2+) mobilization from the SR into both the cytosol and mitochondria. Treatment of cardiomyocytes with SA4503 largely restored PE-induced Ca(2+) mobilization into mitochondria. Exposure of cardiomyocytes to Ang II for 72h 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.
AuthorsHideaki Tagashira, Chen Zhang, Ying-Mei Lu, Hideyuki Hasegawa, Hiroshi Kanai, Feng Han, Kohji Fukunaga
JournalBiochimica et biophysica acta (Biochim Biophys Acta) Vol. 1830 Issue 4 Pg. 3082-94 (Apr 2013) ISSN: 0006-3002 [Print] Netherlands
PMID23298811 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
CopyrightCopyright © 2012 Elsevier B.V. All rights reserved.
Chemical References
  • Inositol 1,4,5-Trisphosphate Receptors
  • Ip3r2 protein, mouse
  • Piperazines
  • Receptors, sigma
  • Adenosine Triphosphate
  • SA 4503
  • Calcium
Topics
  • Adenosine Triphosphate (biosynthesis)
  • Animals
  • Calcium (metabolism)
  • Cardiomegaly (drug therapy, metabolism)
  • Inositol 1,4,5-Trisphosphate Receptors (analysis)
  • Male
  • Mice
  • Mice, Inbred ICR
  • Mitochondria (metabolism)
  • Piperazines (pharmacology, therapeutic use)
  • Receptors, sigma (agonists, analysis, physiology)

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