title: [Cardioprotective effect of the selective sigma-1 receptor agonist, SA4503].
abstract: 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 μM) dose-dependently inhibited hypertrophy in cultured cardiomyocytes induced by angiotensin II (Ang II). We also found that α1 receptor stimulation by phenylephrine (PE) promotes ATP production through IP3 receptor-mediated Ca(2+) 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 Ca(2+) 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.
authors.affiliation: Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Tohoku University.
authors.forename: Kohga
authors.initials: K
authors.lastname: Hirano
authors.forename: Hideaki
authors.initials: H
authors.lastname: Tagashira
authors.forename: Kohji
authors.initials: K
authors.lastname: Fukunaga
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D006332:Cardiomegaly / Q000188:drug therapy* / Q000503:physiopathology; D006801:Humans; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000187:drug effects*; D010879:Piperazines / Q000737:chemistry / Q000494:pharmacology*; D017480:Receptors, sigma / Q000819:agonists*; D000097605:Sigma-1 Receptor
chemical_list: D002118:Calcium; D010879:Piperazines; D017480:Receptors, sigma; D000097605:Sigma-1 Receptor; C101789:SA 4503