Regulation of cardiac myocyte protein synthesis through phosphatidylinositol 3′ kinase and protein kinase B

Although an increase in protein synthesis is a key factor in cardiac hypertrophy, the intracellular signaling pathways which regulate this response are only now emerging. As in other cells, cardiac myocyte protein synthesis is stimulated by the PI3K pathway in both the basal state and in growth responses triggered by insulin or hypertrophic agents such as PE. Oxidative stress stimulates PI3K activity and phosphorylation of PKB in cardiac myocytes, but global protein synthesis is effectively switched off during the apoptotic response. This effect is probably mediated by increased phosphatase activity which promotes dephosphorylation of 4E-BP1 to increase its inhibitory effect on the translation initiation factor eIF4E. In spite of the inhibition of global protein synthesis by oxidative stress, specific proteins such as p21CIPI may still be upregulated, presumably to allow apoptosis to proceed or to aid recovery of the cell. Although the PI3K pathway is obviously important in the regulation of protein synthesis in cardiac myocytes, other intracellular signalling pathways may also promote protein synthesis. For example, phosphorylation of eIF4E downstream from the ERK cascade may be important when considering hypertrophic stimuli such as phorbol esters or ET-1 which very potently activated this pathway. The convergence of the different signaling pathways of different parts of the synthetic machinery will determine the overall level of protein synthesis in cardiac pathologies.