Abstract 18263: GSK3β Inhibits Cardiac Hypertrophy through FoxO1, but Protects the Heart from Dysfunction Independently of FoxO1 under Pressure Overload
Both glycogen synthase kinase-3β (GSK-3β), a serine/threonine kinase, and FoxO1, a member of the FoxO family of transcription factors, negatively regulate cardiac hypertrophy. We have shown previously that GSK-3β physically interacts with and phosphorylates FoxO1 and that GSK-3β induces nuclear translocation of FoxO1 in cultured cardiomyocytes (CMs) in vitro. In order to elucidate the role of FoxO1 in mediating the effect of GSK-3β upon cardiac responses in vivo, we generated a genetic cross (β-KI-KO mice) between GSK-3β (S9A) knock-in (β-KI) mice, in which GSK-3β is constitutively active, and cardiac specific FoxO1 KO (c-FoxO1-KO) mice, in which cardiac specific deletion of FoxO1 was achieved via αMHC-Cre. We have shown previously that transverse aortic constriction (TAC)-induced cardiac hypertrophy and left ventricular (LV) dysfunction were significantly attenuated in β-KI mice. The cardiac phenotype of the β-KI-KO mice was normal at baseline. After 2 weeks of pressure overload (PO) achieved by TAC, LV weight/tibial length was significantly smaller in β-KI mice than in wild type (WT) mice (mg/mm, 5.5±0.3*, 6.4±0.1, *p<0.05) whereas it was significantly greater in β-KI-KO mice (mg/mm, 6.2±0.3*, 5.5±0.3, *p<0.05) than in β-KI mice, suggesting that FoxO1 is required for GSK-3β (S9A) to inhibit cardiac hypertrophy under PO. LV systolic function after TAC was maintained in both β-KI and β-KI-KO mice (72±5%, 65±3%) despite the fact that it was significantly attenuated in c-FoxO1-KO mice (44±1%*, *p<0.05 vs β-KI-KO mice), suggesting that FoxO1 is not required for GSK-3β (S9A) to protect the heart from cardiac dysfunction caused by PO and that GSK-3β (S9A) even protects the heart against dysfunction caused by the lack of FoxO1. Immunostaining of myocardial sections showed that although FoxO1 is localized primarily in the cytosol after TAC, it was localized primarily in the nucleus after TAC in β-KI mice. Taken together, these results suggest that activation of GSK-3β induces nuclear localization of FoxO1, possibly through phosphorylation and that FoxO1 plays an important role in mediating the anti-hypertrophic actions of GSK-3β. However, GSK-3β protects the heart from LV dysfunction under PO independently of FoxO1.
- © 2010 by American Heart Association, Inc.