Abstract 13426: GSK-3β Prevents Cardiac Dysfunction through Modulation of FoxO1 Activity Under Pressure Overload
Both GSK-3β and FoxO1 negatively regulate cardiac hypertrophy. GSK-3β interacts with and phosphorylates FoxO1, thereby inducing nuclear translocation of FoxO1 and FoxO1-mediated transcription in cardiomyocytes (CMs) in vitro. GSK-3β is phosphorylated at Serine 9 in response to pressure overload (PO), and GSK-3β (S9A) knock-in (β-KI) inhibits cardiac hypertrophy and dysfunction in response to PO. In order to test the role of FoxO1 in mediating the salutary effects of GSK-3β (S9A) in vivo, we crossed β-KI mice with cardiac specific FoxO1 KO (c-FoxO1-KO) mice, in which cardiac specific deletion of FoxO1 was achieved via αMHC-Cre, and subjected these mice to transverse aortic constriction (TAC) for 4 weeks. Both cardiac hypertrophy and left ventricular (LV) dysfunction in response to PO were significantly attenuated in β-KI mice, in which GSK-3β is constitutively active, compared to in wild type mice (WT), as indicated by left ventricular weight (LVW) / tibial length (TL) (mg/mm, 6.8±0.4 vs 7.4±0.3, p<0.05) and LV ejection fraction (LVEF) (65±2%, 57±3%). Conversely, LVW/TL was significantly greater (8.2±0.2, p<0.05 vs WT) and LVEF was significantly lower (45±4%, p<0.05 vs WT) in c-FoxO1-KO mice than in WT mice, suggesting that endogenous FoxO1 negatively regulates cardiac hypertrophy in response to PO. In β-KI/c-FoxO1-KO genetically crossed mice (β-KI-KO), LVW/TL was significantly greater (7.6±0.6, p<0.05 vs β-KI) than in β-KI mice, suggesting that endogenous FoxO1 is required for GSK-3β (S9A) to inhibit cardiac hypertrophy under PO. LVEF in β-KI-KO was significantly lower than that in β-KI (53±3%, p<0.05 vs β-KI), suggesting that endogenous FoxO1 is required for the protection against cardiac dysfunction during PO observed in β-KI. Although FoxO1 is localized primarily in the cytosol after TAC in WT mice, it was localized in the nucleus after TAC in β-KI mice. Taken together, these results suggest that GSK-3β (S9A) induces nuclear localization of FoxO1, possibly through phosphorylation, that FoxO1 plays an important role in mediating the anti-hypertrophic and cardioprotective actions of GSK-3β (S9A), and that PO-induced phosphorylation of GSK-3β mediates pathological hypertrophy by abolishing the salutary effect of FoxO1.
- © 2011 by American Heart Association, Inc.