Characterization of MAP kinase and PKC isoform and effect of ACE inhibition in hypertrophy in vivo

Protein kinase C (PKC) and mitogen-activated protein (MAP) kinase activatio n appear important in conferring hypertrophy in vitro. However, the respons e of PKC and MAP kinase to stimuli known to induce hypertrophy in vivo has not been determined. We recently demonstrated that pressure-overload hypert rophy induced a transiently transfected gene driven by an hypertrophy respo nsive enhancer (HRE) through a marked increase in binding activity of its i nteracting nuclear factor (HRF). These data suggested that the HRE/HRF coul d serve as a target for evaluating the signal transduction events responsib le for hypertrophy in vivo. Accordingly, we characterized MAP kinase and PK C isoform activation, injected HRE driven reporter gene expression, and HRF binding activity in rat hearts subjected to ascending aortic clipping or s ham operation in the presence of the angiotensin-converting enzyme (ACE) in hibitor fosinopril, hydralazine, or no treatment. Analyses showed that PKC- epsilon and MAP kinase were acutely activated following ascending aortic li gature and that fosinopril significantly inhibited but did not completely a brogate PKC-epsilon and MAP kinase activation. However, fosinopril complete ly prevented pressure overload-mediated induction of HRE containing constru cts and obviated increased HRF binding activity. These results suggest a di rect relationship between ACE activity and HRE/HRF-mediated gene activation and imply that PKC-epsilon and MAP kinase may be involved in transducing t his signal.