Modulation of the beta-adrenergic response of cardiomyocytes by specific lipoxygenase products involves their incorporation into phosphatidylinositol and activation of protein kinase C.
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.
Wallukat
G
G
Department of Cardiovascular Research, Max-Dehlbrück-Centre for Molecular Medicine, Berlin, FRG.
Morwinski
R
R
Kühn
H
H
D000818:Animals; D001093:Arachidonate 15-Lipoxygenase / Q000378:metabolism*; D002478:Cells, Cultured; D004789:Enzyme Activation; D006321:Heart / Q000187:drug effects; D006893:Hydroxyeicosatetraenoic Acids / Q000494:pharmacology; D009206:Myocardium / Q000166:cytology / Q000201:enzymology / Q000378:metabolism*; D010716:Phosphatidylinositols / Q000378:metabolism*; D011493:Protein Kinase C / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D011943:Receptors, Adrenergic, beta / Q000378:metabolism*; D015398:Signal Transduction
D006893:Hydroxyeicosatetraenoic Acids; D010716:Phosphatidylinositols; D011943:Receptors, Adrenergic, beta; C025984:15-hydroxy-5,8,11,13-eicosatetraenoic acid; D001093:Arachidonate 15-Lipoxygenase; D011493:Protein Kinase C