Abstract 12174: Cardiomyocyte-Specific Silencing of Foxo1 Blunts Pressure Overload-Induced Pathological Cardiac Remodeling
Introduction: Forkhead box-containing O (FoxO) transcription factors are critical regulators of a wide range of cellular responses. We recently reported that persistent activation of FoxO1 is a central element in the pathogenesis of diabetic cardiomyopathy. We hypothesized that FoxO1 may also play an essential role in the development of pressure overload-induced cardiac hypertrophy.
Methods and Results: Two month oldwild-type (WT) and cardiomyocyte-specific FoxO1 knockout (cKO) mice were subjected to sham or thoracic aortic constriction (TAC) surgery for 3 weeks. WT mice manifested significant cardiac hypertrophic growth, as evidenced by increased heart weight/body weight ratios and cardiomyocyte cross-sectional areas. By contrast, hypertrophic growth was significantly blunted in cKO mice. Importantly, WT, but not cKO, mice manifested diminished contractile function, including diminished % fractional shortening and increased left ventricular dimensions in systole and diastole, as judged by M-mode echocardiography. Histological and gene expression data revealed a significant TAC-induced increase in fibrosis and a robust induction of fetal gene expression in WT, but not cKO, heart. Consistent with these in vivo data, siRNA-mediated knockdown of FoxO1 in cultured neonatal rat ventricular cardiomyocytes attenuated hormone-induced fetal gene expression and leucine incorporation.
Conclusions: These data uncover a previously unrecognized role of FoxO1 in afterload-induced pathological remodeling of the adult heart.
- © 2013 by American Heart Association, Inc.