© 2003 by European Society of Cardiology
Copyright © 2003, European Society of Cardiology
Protein kinase C βII activation induces angiotensin converting enzyme expression in neonatal rat cardiomyocytes
Cardiovascular Research, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285, USA
* Corresponding author. Tel.: +1-317-277-6767; fax: +1-317-433-2815. jyw{at}lilly.com
Objective: Members of the protein kinase C (PKC) family are important mediators of cell signaling underlying multiple aspects of myocardial function. Activation of the βII isoform of PKC is thought to be involved in the development of congestive heart failure. To investigate the biological effect of PKC-βII, we measured gene expression of angiotensin converting enzyme (ACE) and angiotensin II (AngII) receptors AT1A and AT1B in cardiomyocytes overexpressing PKC-βII. Methods: An adenovirus construct expressing PKC-βII was introduced into cultured neonatal rat ventricular myocytes (NRVMs). Western blot and in situ kinase assay was used to measure PKC-βII level and activity in NRVMs. Real time quantitative reverse transcription-polymerase chain reaction (RT-PCR) analysis was used to measure the mRNA levels of several genes following PMA stimulation of either un-infected or ad-PKC-βII infected cells. Results: Our data show that activation of PKC-βII in cardiomyocytes leads to elevated expression of angiotensin-converting enzyme (ACE) gene. Treatment of adeno-PKC-βII infected cardiomyocytes with phorbol 12-myristate 13-acetate (PMA) resulted in an 8-fold increase of ACE mRNA expression, whereas ACE mRNA levels only increased around 2-fold in uninfected or adeno-GFP (green fluorescent protein) infected cardiomyocytes with similar PMA treatment. The induction of ACE mRNA was blocked by the PKC-β-specific antagonist LY379196. No significant change of angiotensin II receptors AT1a and AT1b could be detected in the cardiomyocytes expressing PKC-βII. Conclusion: These data indicate that ACE is a transcription target of PKC-βII activation in cardiomyocytes, and also suggest a mechanism for the involvement of PKC in cardiac hypertrophy and fibrosis through increased activity of angiotensin converting enzyme in the myocardium.
KEYWORDS Gene expression; Heart failure; Protein kinases; Renin angiotensin system
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