Abstract 12840: In vivo Visualization of ATP Dynamics Under Hypoxia Reveals That G0/G1 Switch Gene 2 Provides Ischemic Tolerance Through the Increase of ATP Production
Introduction: We have recently established the method for the selective measurement of intra-mitochondrial ATP levels ([ATP]mito) and have identified the hypoxia-inducible protein G0/G1 switch gene 2 (G0s2) as a positive regulator of mitochondrial oxidative phosphorylation by cultured cardiomyocyte-based experiments. However, the energy metabolism in cultured cells may be much different from that in the living tissue. In this study, we examined the in vivo role of G0s2 under hypoxia by using a novel real-time in vivo ATP imaging technique in zebrafish heart.
Methods and Results: We first established the in vivo ATP imaging technique by introducing a FRET-based ATP biosensor named Mit-ATeam into zebrafish heart (Mit-ATeam zebrafish). This system also allows us the simultaneous evaluation of cardiac function. Using Mit-ATeam zebrafish, we successfully observed a decline in [ATP]mito and cardiac function under hypoxic stress and the recovery of these parameters by sequential re-oxygenation. Cardiac specific G0s2 transgenic zebrafish had significantly stronger tolerance against hypoxic stress than wild type zebrafish, while mutant G0s2 transgenic zebrafish did not. In addition, we generated a chimeric zebrafish model in which G0s2 was regionally overexpressed to examine whether focal overexpression of G0s2 could preserve regional cardiac function under hypoxia. Only G0s2-overexpressing cardiomyocyte populations showed enhanced contractility with increased [ATP]mito in hypoxia compared to the control region (i.e. non-G0s2-overexpressing cardiomyocyte populations). Furthermore, we detected enhanced protein expression of G0s2 protein in the risk area in canine ischemic preconditioned heart, suggesting the possible involvement of G0s2 in ischemic preconditioning mediated cardioprotection.
Conclusions: These results suggest that G0s2 functions as a guardian of ischemic myocardium and could become a therapeutic target for ischemic heart diseases. Additionally, this study is the first to connect cardiac energy metabolism and function in living animal in real-time.
Author Disclosures: H. Kioka: None. H. Kato: None. Y. Asano: None. Y. Sakata: None. M. Kitakaze: None. S. Takashima: None.
- © 2014 by American Heart Association, Inc.