Abstract 12636: FoxO1 Attenuates Physiological Cardiac Hypertrophy
Akt1 signaling has been shown to be required for exercise-induced cardiac hypertrophy, but targets downstream of the protein kinase directly affecting cardiac myocyte physiology remain uncertain. The FoxO family of transcription factors acts to coordinate the expression of a variety of genes involved in cell growth, proliferation, survival and metabolism. FoxO proteins are negatively regulated by Akt, and studies report that overexpression of FoxO1 in vitro prevents angiotensin-induced hypertrophy. However, little is known regarding the requirement for cardiac FoxO1 in vivo because FoxO1−/− animals die during development due to vascular malformations. To evaluate whether FoxO1 plays a critical role in cardiac physiology, we have developed a cardiac-specific tamoxifen-inducible FoxO1 KO mouse to investigate the role of FoxO1 in physiological cardiac hypertrophy. At 8 weeks of age, αMHC-MerCreMer+/− FoxO1loxP/loxP (FoxO1 iCKO) mice and αMHC-MerCreMer+/− mice, used as controls throughout experimentation, were administered tamoxifen to induce knockout. At 12 weeks of age, FoxO1 expression was significantly reduced in FoxO1 iCKO animals, however there was no difference in left ventricle to body weight (LV/BW) ratios between FoxO1 iCKO and controls (3.35 ± 0.11 and 3.45 ± 0.05, respectively). Next, FoxO1 iCKO and control mice were subjected to three weeks of swim training, swimming up to 90 minutes two times daily. At the end of swim training, no significant functional differences were detected by echocardiography, but FoxO1 iCKO mice developed significantly greater LV hypertrophy relative to controls (LV/BW ratios of 4.06 ± 0.27 and 3.66 ± 0.23, respectively; p=0.007). Furthermore, known FoxO1-regulated anti-hypertrophy genes atrogin-1 and muscle ring finger-1 were significantly reduced in FoxO1 KO mice (29% and 60% reduction, respectively). Taken together, these data suggest FoxO1 can attenuate exercise-induced cardiac hypertrophy, in part through regulation of anti-hypertrophic genes.
- © 2010 by American Heart Association, Inc.