Stimulation of σ1-receptor restores abnormal mitochondrial Ca²âº mobilization and ATP production following cardiac hypertrophy.
Biochim Biophys Acta
; 1830(4): 3082-94, 2013 Apr.
Article
en En
| MEDLINE
| ID: mdl-23298811
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. GENERALSIGNIFICANCE:
Our observations suggest that σ1R stimulation represents a new therapeutic strategy to rescue the heart from hypertrophic dysfunction.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Piperazinas
/
Adenosina Trifosfato
/
Calcio
/
Receptores sigma
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Cardiomegalia
/
Mitocondrias
Límite:
Animals
Idioma:
En
Revista:
Biochim Biophys Acta
Año:
2013
Tipo del documento:
Article
País de afiliación:
Japón