Protein kinase C- -induced hypertrophy of neonatal rat ventricular myocytes

Vijayan, Kalpana, Erika L. Szotek, Jody L. Martin, and Allen M. Samarel. Protein kinase C-induced hypertrophy of neonatal rat ventricular myocytes. Am J Physiol Heart Circ Physiol 287: H2777– H2789, 2004. First published July 22, 2004; doi:10.1152/ajpheart. 00171.2004.—Protein kinase C (PKC) isoenzymes play a critical role in cardiomyocyte hypertrophy. At least three different phorbol estersensitive PKC isoenzymes are expressed in neonatal rat ventricular myocytes (NRVMs): PKC, , and . Using replication-defective adenoviruses (AdVs) that express wild-type (WT) and dominantnegative (DN) PKCtogether with phorbol myristate acetate (PMA), which is a hypertrophic agonist and activator of all three PKC isoenzymes, we studied the role of PKCin signaling-specific aspects of the hypertrophic phenotype. PMA induced nuclear translocation of endogenous and AdV-WT PKCin NRVMs. WT PKCoverexpression increased protein synthesis and the protein-to-DNA (P/D) ratio but did not affect cell surface area (CSA) or cell shape compared with uninfected or control AdV -galactosidase (AdV gal)-infected cells. PMA-treated uninfected cells displayed increased protein synthesis, P/D ratio, and CSA and elongated morphology. PMA did not further enhance protein synthesis or P/D ratio in AdV-WT PKC-infected cells. To assess the requirement of PKCfor these PMA-induced changes, AdV-DN PKCor AdV galinfected NRVMs were stimulated with PMA. Without PMA, AdV-DN PKChad no effects on protein synthesis, P/D ratio, CSA, or shape vs. AdV gal-infected NRVMs. PMA increased protein synthesis, P/D ratio, and CSA in AdV gal-infected cells, but these parameters were significantly reduced in PMA-stimulated AdV-DN PKC-infected NRVMs. Overexpression of DN PKCenhanced PMA-induced cell elongation. Neither WT PKCnor DN PKCaffected atrial natriuretic factor gene expression. Insulin-like growth factor-1 also induced nuclear translocation of endogenous PKC. PMA but not WT PKCoverexpression induced ERK1/2 activation. However, AdV-DN PKCpartially blocked PMA-induced ERK activation. Thus PKCis necessary for certain aspects of PMAinduced NRVM hypertrophy.