Abstract 17567: Stanniocalcin-1 Induces A Novel Anti-Oxidant Pathway in Cardiomyocytes

Abstract

Rationale: We have shown increased cardiac stanniocalcin-1 (STC1) in patients with idiopathic dilated cardiomyopathy. STC1 localizes to the inner mitochondrial, and transgenic overexpression of STC1 is associated with increased energy utilization. Objective: We examined the hypothesis that STC1 uncouples mitochondrial oxidative phosphorylation - to affect energy metabolism and superoxide generation in cardiomyocytes. Methods and Results: Compared to WT mouse heart, STC1 Tg heart displays 2-fold higher uncoupling protein 3 (UCP3) levels, 40% lower ATP levels, but similar activities of respiratory chain complexes I-IV. In cultured adult rat cardiomyocytes, recombinant hSTC1 is internalized by cultured rat cardiomyocytes and is targeted to the mitochondria within minutes; it induces UCP3, decreases mitochondrial membrane potential and suppresses baseline and ANG II-provoked superoxide generation. In freshly-isolated adult mouse cardiomyocytes, STC1 diminishes baseline and ANG II-induced superoxide generation equally in WT and gp91 phox -/- cardiomyocytes, suggesting gp91phox-independent mechanism of action. Baseline superoxide generation is higher in freshly-isolated adult UCP3 -/- mouse cardiomyocytes, compared to WT; and, treatment of UCP3 -/- cardiomyocytes with STC1 failed to suppress superoxide generation in the presence or absence of ANG II, suggesting that the effects of STC1 on superoxide generation are UCP3-mediated. Conclusion: STC1 activates a novel anti-oxidant pathway in cardiac myocytes through induction of UCP3; this pathway may play an important role in regulating reactive oxygen species in the heart under normal physiologic and pathophysiologic conditions, and ameliorate the deleterious effects of ANG II-mediated cardiac injury.