Key result
Fosinopril significantly inhibited PKC-epsilon and MAP kinase activation and completely prevented pressure overload-mediated induction of HRE containing constructs and increased HRF binding activity.
ACE inhibition with fosinopril prevents pressure overload-mediated gene activation in vivo, suggesting a direct relationship between ACE activity and HRE/HRF-mediated gene activation involving PKC-epsilon and MAP kinase.
Extends in vitro hypertrophy signaling concepts to pressure-overload models; leaves open PKC/MAP kinase mediation in vivo.
Protein kinase C (PKC) and mitogen-activated protein (MAP) kinase activation appear important in conferring hypertrophy in vitro. However, the response of PKC and MAP kinase to stimuli known to induce hypertrophy in vivo has not been determined. We recently demonstrated that pressure-overload hypertrophy induced a transiently transfected gene driven by an hypertrophy responsive enhancer (HRE) through a marked increase in binding activity of its interacting nuclear factor (HRF). These data suggested that the HRE/HRF could serve as a target for evaluating the signal transduction events responsible for hypertrophy in vivo. Accordingly, we characterized MAP kinase and PKC isoform activation, injected HRE driven reporter gene expression, and HRF binding activity in rat hearts subjected to ascending aortic clipping or sham operation in the presence of the angiotensin-converting enzyme (ACE) inhibitor fosinopril, hydralazine, or no treatment. Analyses showed that PKC-epsilon and MAP kinase were acutely activated following ascending aortic ligature and that fosinopril significantly inhibited but did not completely abrogate PKC-epsilon and MAP kinase activation. However, fosinopril completely prevented pressure overload-mediated induction of HRE containing constructs and obviated increased HRF binding activity. These results suggest a direct relationship between ACE activity and HRE/HRF-mediated gene activation and imply that PKC-epsilon and MAP kinase may be involved in transducing this signal.
No takes yet. Share an insight, caveat, or question.
Kim et al. (1999) studied Pressure-overload hypertrophy. Fosinopril vs. Hydralazine, no treatment, or sham operation was evaluated on PKC-epsilon and MAP kinase activation, HRE driven reporter gene expression, and HRF binding activity. Fosinopril significantly inhibited PKC-epsilon and MAP kinase activation and completely prevented pressure overload-mediated induction of HRE containing constructs and increased HRF binding activity.
Synapse has enriched 5 closely related papers on similar clinical questions. Consider them for comparative context: