Modulation of the beta-adrenergic response of cardiomyocytes by specific lipoxygenase products involves their incorporation into phosphatidylinositol and activation of protein kinase C

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Item Type:	Article
Title:	Modulation of the beta-adrenergic response of cardiomyocytes by specific lipoxygenase products involves their incorporation into phosphatidylinositol and activation of protein kinase C
Creators Name:	Wallukat, G., Morwinski, R. and Kuehn, H.
Abstract:	Arachidonic acid and its 15-lipoxygenase metabolite (15S)-hydroxy-(5Z,8Z,11Z,13E)-eicosatetraenoic acid ((15S)-HETE) modulates the beta-adrenergic response of cultured rat neonatal cardiomyocytes as indicated by an increase in the beating rate following stimulation of the cells with suboptimal isoproterenol concentrations. The effect of 15-HETE was enantioselective for the S-isomer and could be detected at concentrations as low as 10(-12) M. (11S)-HETE and (5S,15S)-dihydroxy-(6E,8Z,11Z,13E)-eicosatetraen oic acid did also exhibit this effect, whereas other mono-, di-, and trihydroxyeicosanoids as well as the 15-lipoxygenase products of 11,14-eicosadienoic acid, of two eicosatrienoic acid isomers and of 5,8,11,14,17-eicosapentaenoic acid were ineffective. Immunohistochemical studies indicated the expression of a 15-lipoxygenase in cardiomyocytes and in resident heart mast cells. Induction of the beta-adrenergic supersensitivity is paralleled by a selective incorporation of (15S)-HETE into the cellular phosphatidylinositol pool. In contrast, (12S)-HETE, which did not induce beta-adrenergic supersensitivity, was incorporated preferentially into phosphatidylcholine and phosphatidylethanolamine. Calphostin C, an inhibitor of protein kinase C, blocked both the induction of supersensitivity by (15S)-HETE and its incorporation into phosphatidylinositol. These data suggest that in cardiomyocytes 15-lipoxygenase metabolites specifically induces a signal transduction cascade leading to a supersensitivity of the cells toward beta-adrenergic agonists, which involves the phosphatidylinositol cycle and a protein kinase C.
Keywords:	Arachidonate 15-Lipoxygenase, beta Adrenergic Receptors, Cultured Cells, Enzyme Activation, Heart, Hydroxyeicosatetraenoic Acids, Myocardium, Phosphatidylinositols, Protein Kinase C, Signal Transduction, Animals, Rats
Source:	Journal of Biological Chemistry
ISSN:	0021-9258
Publisher:	American Society for Biochemistry and Molecular Biology
Volume:	269
Number:	46
Page Range:	29055-29060
Date:	18 November 1994
Official Publication:	http://www.jbc.org/content/269/46/29055.abstract
PubMed:	View item in PubMed

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