3051
DELETION OF THE TRANSLATIONAL REPRESSORS EUKARYOTIC
TRANSLATION INITIATION FACTOR 4E BINDING PROTEINS 1 AND 2
PROTECTS AGAINST PRESSURE OVERLOAD INDUCED HEART FAILURE
Z. Lu1,2, X. Hu1,2, Y. Huang3, X. Xu1, P. Zhang1,2, M. Peterson4, V.A. Polunovsky4,
N. Sonenberg5, R.J. Bache1,2, P.B. Bitterman4, Y. Chen1,2
1. Cardiovascular Division, and 2. Lillehei Heart Institute, University of Minnesota
Medical School, Minneapolis, MN. USA
3. Molecular and Cellular Biology Laboratory, Beijing Anzhen Hospital,
Capital Medical University, China.
4. Pulmonary Division, University of Minnesota Medical School, Minneapolis,
MN, USA
5. Department of Biochemistry, McGill University, Montreal, Quebec, Canada
Assembly of the translation initiation machinery is negatively regulated by the eukaryotic
translation initiation factor 4E binding proteins, which sequester the mRNA cap-binding
protein eIF4E, thus preventing assembly of an intact initiation complex. However, the
role of translational control on the development of congestive heart failure (CHF) has not
been systematically examined. Here we perturbed translational control in mice by
knockout of both 4E binding protein 1 (Eif4ebp1) and 2 (Eif4ebp2) (designated as
Eif4ebp1/2 double knockout) to study its impact on left ventricular hypertrophy and CHF
resulting from transverse aortic constriction. Eif4ebp1/2 double knockout caused a
modest increase in left ventricular mass under basal conditions. However, following
transverse aortic constriction, Eif4ebp1/2 double knockout profoundly attenuated the
development of CHF and its attendant mortality. Examination of candidate genes
involved in the mechanism revealed increased expression of transcription factors for
genes governing energy metabolism and mitochondrial biogenesis with corresponding
increases in the expression of their target genes. Our data indicate that removing
physiological restraints on translation initiation exerts a profound cardiac protective
effect against pressure overload induced CHF, suggesting that method(s) to disrupt the
function of the 4E binding proteins may be a novel therapeutic approach for preventing or
treating CHF.