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RECEPTORS AND SIGNAL TRANSDUCTION

Isoenzyme-selective regulation of SERCA2 gene expression by protein kinase C in neonatal rat ventricular myocytes

The Cardiovascular Institute and Departments of ¹Medicine and ²Physiology, Loyola University Chicago Stritch School of Medicine, Maywood, Illinois 60153

Submitted 2 October 2002 ; accepted in final form 25 February 2003

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 (PKC, PKC, and PKC), 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 PKC, PKC, and PKC to analyze their individual effects in regulating SERCA2 gene expression in NRVM. Overexpression of wtPKC and wtPKC, but not wtPKC, 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 and wtPKC, respectively; P < 0.05 for each adenovirus; n = 8 experiments). Conversely, overexpression of all three dnPKCs appeared to significantly increase SERCA2 mRNA levels (dnPKC > dnPKC > dnPKC). dnPKC 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 PKC and PKC 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.

heart; signal transduction; hypertrophy; transcription; mRNA stability; sarco(endo)plasmic reticulum Ca²⁺-ATPase

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