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 (0.1-1μM) 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.
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Authors | Hideaki Tagashira, Chen Zhang, Ying-Mei Lu, Hideyuki Hasegawa, Hiroshi Kanai, Feng Han, Kohji Fukunaga |
Journal | Biochimica et biophysica acta
(Biochim Biophys Acta)
Vol. 1830
Issue 4
Pg. 3082-94
(Apr 2013)
ISSN: 0006-3002 [Print] Netherlands |
PMID | 23298811
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Copyright | Copyright © 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
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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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