title: Na(+)influx via Na(+)/H(+)exchange activates protein kinase C isozymes delta and epsilon in cultured neonatal rat cardiac myocytes.
abstract: Protein kinase C (PKC) is one of the important signaling molecules in the development of the cardiac hypertrophic response, and activation of Na(+)/H(+)exchange is caused by PKC in myocytes. In this study we examined the contribution of Na(+)/H(+)exchange in cardiac hypertrophy induced by the activation of PKC and its mechanism using cultured neonatal rat cardiac myocytes. Phenylephrine (PE), endothelin-1 (ET-1) and phorbol 12-myristate 13-acetate (PMA) increased cytoplasmic pH in myocytes, and this effect was strongly inhibited by treatment with HOE694, an inhibitor of Na(+)/H(+)exchange. These substances increased the [(3)H]phenylalanine incorporation, total protein content and beta -myosin heavy chain protein content in myocytes. These hypertrophic responses were also attenuated by HOE694. To clarify the role of Na(+)influx through activation of Na(+)/H(+)exchange in cardiac hypertrophy, we next examined the hypertrophic responses to veratridine and ouabain, which increase the intracellular Na(+)content. Veratridine and ouabain increased the [(3)H]phenylalanine incorporation. Staurosporine, a PKC inhibitor, completely abolished veratridine-induced hypertrophic response, but did not affect increment of intracellular Na(+)concentration by veratridine. PMA caused increases of alpha -, delta -and epsilon -PKC in the particulate fraction, but PE, ET-1 and veratridine affected only those of delta - and epsilon -PKC. HOE694 significantly inhibited only increases of delta - and epsilon -PKC caused by PE, ET-1 or PMA, but not those by veratridine. These results demonstrate that Na(+)influx via activation of Na(+)/H(+)exchange reactivates PKC in myocytes. delta - and epsilon -PKC appear to be involved in the signal mechanism of the hypertrophic response induced by Na(+)influx through Na(+)/H(+)exchange in myocytes.
authors.affiliation: Discovery Research Laboratories, Shionogi & Co Ltd, 3-1-1 Futaba-cho, Toyonaka, Osaka, 561-0825, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Hayasaki-Kajiwara
authors.forename: Y
authors.initials: Y
authors.lastname: Kitano
authors.forename: T
authors.initials: T
authors.lastname: Iwasaki
authors.forename: T
authors.initials: T
authors.lastname: Shimamura
authors.forename: N
authors.initials: N
authors.lastname: Naya
authors.forename: K
authors.initials: K
authors.lastname: Iwaki
authors.forename: M
authors.initials: M
authors.lastname: Nakajima
mesh_terms: D000818:Animals; D002273:Carcinogens / Q000494:pharmacology; D048429:Cell Size; D002478:Cells, Cultured; D019332:Endothelin-1 / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects; D006146:Guanidines / Q000494:pharmacology; D006352:Heart Ventricles / Q000378:metabolism* / Q000473:pathology; D006863:Hydrogen-Ion Concentration; D017136:Ion Transport / Q000187:drug effects; D007527:Isoenzymes / Q000378:metabolism*; D010656:Phenylephrine / Q000494:pharmacology; D011493:Protein Kinase C / Q000378:metabolism*; D051745:Protein Kinase C-delta; D051744:Protein Kinase C-epsilon; D051381:Rats; D017207:Rats, Sprague-Dawley; D012964:Sodium / Q000378:metabolism*; D017923:Sodium-Hydrogen Exchangers / Q000378:metabolism; D013450:Sulfones / Q000494:pharmacology; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology
chemical_list: D002273:Carcinogens; D019332:Endothelin-1; D006146:Guanidines; D007527:Isoenzymes; D017923:Sodium-Hydrogen Exchangers; D013450:Sulfones; C074107:3-methylsulfonyl-4-piperidinobenzoyl guanidine; D010656:Phenylephrine; D012964:Sodium; C497260:Prkcd protein, rat; C497257:Prkce protein, rat; D011493:Protein Kinase C; D051745:Protein Kinase C-delta; D051744:Protein Kinase C-epsilon; D013755:Tetradecanoylphorbol Acetate