| First Author | Tagashira H | Year | 2013 |
| Journal | Biochim Biophys Acta | Volume | 1830 |
| Issue | 4 | Pages | 3082-94 |
| PubMed ID | 23298811 | Mgi Jnum | J:199047 |
| Mgi Id | MGI:5500145 | Doi | 10.1016/j.bbagen.2012.12.029 |
| Citation | Tagashira H, et al. (2013) Stimulation of sigma1-receptor restores abnormal mitochondrial Ca(2)(+) mobilization and ATP production following cardiac hypertrophy. Biochim Biophys Acta 1830(4):3082-94 |
| abstractText | BACKGROUND: We previously reported that the sigma1-receptor (sigma1R) is down-regulated following cardiac hypertrophy and dysfunction in transverse aortic constriction (TAC) mice. Here we address how sigma1R stimulation with the selective sigma1R agonist SA4503 restores hypertrophy-induced cardiac dysfunction through sigma1R localized in the sarcoplasmic reticulum (SR). METHODS: We first confirmed anti-hypertrophic effects of SA4503 (0.1-1muM) in cultured cardiomyocytes exposed to angiotensin II (Ang II). Then, to confirm the ameliorative effects of sigma1R stimulation in vivo, we administered SA4503 (1.0mg/kg) and the sigma1R antagonist NE-100 (1.0mg/kg) orally to TAC mice for 4weeks (once daily). RESULTS: sigma1R 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: sigma1R stimulation with the specific agonist SA4503 ameliorates cardiac hypertrophy and dysfunction by restoring both mitochondrial Ca(2+) mobilization and ATP production via sigma1R stimulation. GENERAL SIGNIFICANCE: Our observations suggest that sigma1R stimulation represents a new therapeutic strategy to rescue the heart from hypertrophic dysfunction. |
