Journal
YAKUGAKU ZASSHI-JOURNAL OF THE PHARMACEUTICAL SOCIETY OF JAPAN
Volume 134, Issue 6, Pages 707-713Publisher
PHARMACEUTICAL SOC JAPAN
DOI: 10.1248/yakushi.13-00255-3
Keywords
sigma-1 receptor; cardiac hypertrophy; mitochondria; ATP production
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We previously reported that the sigma-1 receptor is down-regulated in cardiomyocytes following heart failure in transverse aortic constriction (TAC) mice. In this review, we summarized the anti-hypertrophic action of selective sigma-1 receptor agonist, SA4503 in the hypertrophied cultured cardiomyocytes and discussed its possible mechanism of cardioprotection. Treatment with SA4503 (0.1-1 mu m) dose-dependently inhibited hypertrophy in cultured cardiomyocytes induced by angiotensin II (Ang II). We also found that alpha(1) receptor stimulation by phenylephrine (PE) promotes ATP production through IP3 receptor-mediated Ca2+ mobilization into mitochondria in cultured cardiomyocytes. Interestingly, the PE-induced ATP production was impaired after Ang II-induced hypertrophy and SA4503 treatment largely restored PE-induced ATP production. The impaired PE-induced ATP production was associated with reduced mitochondrial size. The SA4503 treatment completely restored mitochondrial size concomitant with restored ATP production. These effects were blocked by sigma-1 receptor antagonist, NE-100 and sigma-1 receptor siRNA. We also confirmed that chronic SA4503 administration also significantly attenuates myocardial hypertrophy and restores ATP production in transverse aortic constriction mice. Taken together, sigma-1 receptor stimulation with selective agonist SA4503 ameliorates cardiac hypertrophy and dysfunction by restoring both mitochondrial Ca2+ mobilization and ATP production via sigma-1 receptor stimulation. Sigma-1 receptor stimulation represents a new therapeutic strategy to rescue heart from hypertrophic dysfunction in heart failure.
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