Abstract 4: The Mitochondrial Ca2+ Transport and ATP Production Through Sigma-1 Receptor in Heart
Objective: Although sigma-1 receptor is originally postulated as an opioid receptor in the central nervous system, we recently defined the higher expression of sigma-1 receptor in cardiac ventricle and kidney as compared to brain tissues (Expert Opin Ther Targets 2010;14:1009-1022). To address the question whether mitochondrial Ca2+transport and ATP production in heart are regulated by sigma-1 receptor stimulation, we tested the anti-hypertrophic effects of the specific sigma-1 receptor agonist, SA4503 in transverse aortic constriction (TAC) mice.
Methods: We treated mice with SA4503 (0.1, 0.3 and 1.0 mg/kg) orally once a day for 4 weeks after TAC. The cardiac constriction was monitored by echocardiography. The mitochondrial Ca2+ transport and ATP production with or without SA4503 treatment were measured in cultured neonatal cardiomyocytes.
Results: The sigma-1 receptor expression in the left ventricle (LV) decreased significantly over the 4 weeks. SA4503 administration significantly attenuated TAC-induced myocardial hypertrophy concomitant with the recovery of sigma-1 receptor expression in LV. SA4503 also ameliorated the impaired LV fractional shortening. We also investigated the role of sigma-1 receptor for sarcoplasmic reticulum (SR)-mitochondrial Ca2+ transport in cultured neonatal rat ventricular cardiomyocytes. Exposure to angiotensin II (Ang II) for 72 hr elicited marked cardiomyocyte hypertrophy and declined phenylephrine (PE)-induced Ca2+ mobilization into cytosol and mitochondria. SA4503 treatment restored significantly the reduced PE-induced Ca2+ mobilization into mitochondria. Importantly, The Ang II-induced hypertrophy in vitro and transverse aortic constriction-induced cardiac dysfunction in vivo were associated with the reduced ATP concentration, which was completely restored by SA4503 treatment. NE-100, a sigma-1 receptor selective antagonist, abolished these effects induced by SA4503.
Conclusion: The specific sigma-1 receptor agonist, SA4503 ameliorates AngII-induced cardiomyocyte hypertrophy and TAC-induced cardiac dysfunction through restoration of SR-mitochondria Ca2+ transport via sigma-1 receptor stimulation, thereby promoting mitochondrial ATP production.
- © 2012 by American Heart Association, Inc.