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Am J Physiol Cell Physiol (February 26, 2003). doi:10.1152/ajpcell.00461.2002
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Submitted on October 2, 2002
Accepted on February 25, 2003

Isoenzyme-Selective Regulation Of SERCA2 Gene Expression by Protein Kinase C In Neonatal Rat Ventricular Myocytes

Michael J Porter1, Maria C Heidkamp1, Brian T Scully1, Nehu Patel1, Jody L Martin2, and Allen M Samarel2*

1 Cardiovascular Institute, Loyola University Chicago Stritch School of Medicine, Maywood, IL, USA; Medicine, Loyola University Chicago Stritch School of Medicine, Maywood, IL, USA
2 Cardiovascular Institute, Loyola University Chicago Stritch School of Medicine, Maywood, IL, USA; Medicine, Loyola University Chicago Stritch School of Medicine, Maywood, IL, USA; Physiology, Loyola University Chicago Stritch School of Medicine, Maywood, IL, USA

* To whom correspondence should be addressed. E-mail: asamare{at}lumc.edu.

Patients with cardiac hypertrophy and heart failure display abnormally slowed myocardial relaxation which is associated with downregulation of SERCA2 gene expression. We previously showed that SERCA2 downregulation can be simulated in cultured neonatal rat ventricular myocytes (NRVM) by treatment with the protein kinase C (PKC) activator phorbol myristate acetate (PMA). However, NRVM express 3 different PMA-sensitive PKC isoenzymes (PKC{alpha}, PKC{epsilon}, and PKC{delta}), which may be differentially regulated and have specific functions in the cardiomyocyte. Therefore in this study we used adenoviral vectors encoding wildtype (wt) and kinase-defective, dominant-negative (dn) mutant forms of PKC{alpha}, PKC{epsilon} and PKC{delta} to analyze their individual effects in regulating SERCA2 gene expression in NRVM. Overexpression of wtPKC{epsilon} and wtPKC{delta}, but not wtPKC{alpha}, was sufficient to downregulate SERCA2 mRNA levels, as assessed by Northern blotting and quantitative, real-time RT-PCR (69±7% and 61±9% of control levels, for wtPKC{epsilon} and wtPKC{delta}, respectively; P<0.05 for each Adv; n=8 experiments). Conversely, overexpression of all 3 dnPKCs appeared to significantly increase SERCA2 mRNA levels (dnPKC{delta}>dnPKC{epsilon}>dnPKC{alpha}). dnPKC{delta} overexpression produced the largest, statistically significant (P<0.05) increase in SERCA2 mRNA levels (2.8±1.0 fold; n=11 experiments). However, PMA treatment was still sufficient to downregulate SERCA2 mRNA levels despite overexpression of each dominant-negative mutant. These data indicate that the novel PKC isoenzymes PKC{epsilon} and PKC{delta} selectively regulate SERCA2 gene expression in cardiomyocytes, but that neither PKC alone is necessary for this effect if the other novel PKC can be activated.




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