Translational control in the rat heart was characterized during acute myocardial ischemia introduced by left coronary artery ligature. Within 10 min of ischemia, eukaryotic (eIF)4E binds to its negative regulator, eIF4E-binding protein-1 (4E-BP1), but the levels of 4E-BP1 are insufficient to disrupt cap-dependent mRNA initiation complexes. However, by 1 h of ischemia, the abundance of the cap-initiation complex protein eIF4G is reduced by relocalization into TIAR protein complexes, triggering 4E-BP1 sequestration of eIF4E and disruption of cap-dependent mRNA initiation complexes. As the heart begins to fail at 6 h, proteolysis of eIF4G is observed, resulting in its depletion and accompanied by limited destruction of 4E-BP1 and eIF4E. eIF4G proteolysis and modest loss of 4E-BP1 are associated with caspase-3 activation and induction of cardiomyocyte apoptotic and necrotic death. Acute heart ischemia therefore downregulates cap-dependent translation through eIF4E sequestration triggered by eIF4G depletion.