Na(+)influx via Na(+)/H(+)exchange activates protein kinase C isozymes delta and epsilon in cultured neonatal rat cardiac myocytes. |
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Authors: | Y Hayasaki-Kajiwara Y Kitano T Iwasaki T Shimamura N Naya K Iwaki M Nakajima |
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Institution: | Discovery Research Laboratories, Shionogi & Co Ltd, 3-1-1 Futaba-cho, Toyonaka, Osaka, 561-0825, Japan. |
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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. |
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