A REQUIREMENT FOR THE RAC1 GTPASE IN THE SIGNAL-TRANSDUCTION PATHWAY LEADING TO CARDIAC MYOCYTE HYPERTROPHY

We have used adenoviral-mediated gene transfer of a constitutively act ive (V12rac1) and dominant negative (N17rac1) isoform of rad to assess the role of this small GTPase in cardiac myocyte hypertrophy. Express ion of V12rac1 in neonatal cardiac myocytes results in sarcomeric reor ganization and an increase in cell size that is indistinguishable from ligand-stimulated hypertrophy. In addition, V12rac1 expression leads to an increase in atrial natriuretic peptide secretion. In contrast, e xpression of N17rac1, but not a truncated form of Raf-1, attenuated th e morphological hypertrophy associated with phenylephrine stimulation. Consistent with the observed effects on morphology, expression of V12 rac1 resulted in an increase in new protein synthesis, while N17rac1 e xpression inhibited phenylephrine-induced leucine incorporation. These results suggest rad is an essential element of the signaling pathway leading to cardiac myocyte hypertrophy.