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  • Title: Isoenzyme-selective regulation of SERCA2 gene expression by protein kinase C in neonatal rat ventricular myocytes.
    Author: Porter MJ, Heidkamp MC, Scully BT, Patel N, Martin JL, Samarel AM.
    Journal: Am J Physiol Cell Physiol; 2003 Jul; 285(1):C39-47. PubMed ID: 12606313.
    Abstract:
    Patients with cardiac hypertrophy and heart failure display abnormally slowed myocardial relaxation, which is associated with downregulation of sarco(endo)plasmic reticulum Ca2+-ATPase (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 12-myristate 13-acetate (PMA). However, NRVM express three different PMA-sensitive PKC isoenzymes (PKCalpha, PKCepsilon, and PKCdelta), which may be differentially regulated and have specific functions in the cardiomyocyte. Therefore, in this study we used adenoviral vectors encoding wild-type (wt) and kinase-defective, dominant negative (dn) mutant forms of PKCalpha, PKCepsilon, and PKCdelta to analyze their individual effects in regulating SERCA2 gene expression in NRVM. Overexpression of wtPKCepsilon and wtPKCdelta, but not wtPKCalpha, 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 wtPKCepsilon and wtPKCdelta, respectively; P < 0.05 for each adenovirus; n = 8 experiments). Conversely, overexpression of all three dnPKCs appeared to significantly increase SERCA2 mRNA levels (dnPKCdelta > dnPKCepsilon > dnPKCalpha). dnPKCdelta overexpression produced the largest increase (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 PKCepsilon and PKCdelta 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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