Abstract 14662: Loss of the eIf2 Kinase GCN2 Protects Mice From Pressure Overload Induced Congestive Heart Failure
Nutrient deprivation or stress enhances phosphorylation of the alpha subunit of eukaryotic initiation factor 2 (eIF2α) to selectively attenuate mRNA translation through General Control Nonderepressible 2 kinase (GCN2). Phosphorylation of eIF2α is increased in the failing heart, but it is not known whether GCN2 plays a role in the development of left ventricular (LV) hypertrophy or heart failure. To understand the physiological role of GCN2 on LV structure and function, GCN2+/+ and GCN2-/- mice were studied under control conditions and in response to chronic transverse aortic constriction (TAC). Under unstressed conditions GCN2 deficiency had no effect on LV mass or its ratio to body weight, myocyte size, or LV function. However, in response to TAC for 6 weeks, GCN2-deficient mice developed significantly more LV hypertrophy, but less reduction of ejection fraction and less pulmonary congestion than wild type mice. GCN2 deficiency also significantly attenuated TAC-induced increases of ventricular fibrosis and atrial natriuretic peptide. Although GCN2 significantly attenuated ventricular p-eIF2α content, it had no effect on total eIF2α expression or GADD34 expression. Interestingly, GCN2 deficiency significantly attenuated TAC-induced myocyte apoptosis and caspase-3 activation, in association with reduced Bax expression and increased Bcl2 expression. GCN2 also significantly attenuated the TAC-induced increase of CHOP, but had no effect on ventricular ATF4 or GADD34 expression. Collectively, our data indicate that GCN2 deficiency increased TAC-induced LV hypertrophy, but attenuated LV myocyte apoptosis and LV contractile dysfunction by selectively enhancing mRNA translation of a set of protective genes, suggesting that modulating GCN2 signaling might be a novel therapeutic approach for treating congestive heart failure.
- © 2011 by American Heart Association, Inc.