TRANSLATIONAL INITIATION-FACTOR EIF-4E - A LINK BETWEEN CARDIAC LOAD AND PROTEIN-SYNTHESIS

To define the coupling mechanism between cardiac load and the rate of protein synthesis, changes in the extent of eIF-4E phosphorylation wer e measured after imposition of a load. Electrically stimulated contrac tion of adult feline cardiocytes increased eIF-4E phosphorylation to 3 4% after 4 h, as compared with 8% phosphorylation in quiescent control s. However, eIF-4E phosphorylation did not increase upon electrical st imulation in the presence of 7.5 mM 2,3-butanedione monoxime, an inhib itor of actin-myosin cross-bridge cycling and active tension developme nt. Treatment of adult cardiocytes with either 0.1 mu M insulin or 0.1 mu M phorbol 12-myristate 13-acetate increased eIF-4E phosphorylation to 23 and 64%, respectively, but these increases were not blocked by 2,3-butanedione monoxime. In canine models of acute hemodynamic overlo ad in vivo, eIF-4E phosphorylation increased to 23% in response to lef t ventricular pressure overload as compared with 7% phosphorylation in controls. Acute volume overload had no effect on eIF-4E phosphorylati on. These changes in eIF-4E phosphorylation account for differences in anabolic responses to acute pressure versus acute volume overload. Th ese data suggest that eIF-4E phosphorylation is a mechanism by which i ncreased cardiac load is coupled to accelerated rates of protein synth esis.