Endothelin-1 and fibroblast growth factors stimulate the mitogen-activated protein kinase signaling cascade in cardiac myocytes. The potential role of the cascade in the integration of two signaling pathways leading to myocyte hypertrophy

• Published in: The Journal of biological chemistry Vol. 269; no. 2; pp. 1110 - 1119
• Main Authors: BOGOYEVITCH, M. A, GLENNON, P. E, ANDERSSON, M. B, CLERK, A, LAZOU, A, MARSHALL, C. J, PARKER, P. J, SUGDEN, P. H
• Format: Journal Article
• Language: English
• Published: Bethesda, MD American Society for Biochemistry and Molecular Biology 14.01.1994
• Subjects: Animals; Animals, Newborn; Biological and medical sciences; Calcium-Calmodulin-Dependent Protein Kinases - metabolism; Cardiomegaly - enzymology; Cell physiology; Cells, Cultured; Endothelins - pharmacology; Enzyme Activation - drug effects; Fibroblast Growth Factor 1 - pharmacology; Fibroblast Growth Factor 2 - pharmacology; Fundamental and applied biological sciences. Psychology; In Vitro Techniques; Isoenzymes - metabolism; Mitogen-Activated Protein Kinase Kinases; Molecular and cellular biology; Myelin Basic Protein - metabolism; Myocardium - enzymology; Phosphatidylinositols - metabolism; Phosphorylation; Protein Kinase C - physiology; Protein-Serine-Threonine Kinases - metabolism; Protein-Tyrosine Kinases - metabolism; Rats; Responses to growth factors, tumor promotors, other factors; Second Messenger Systems; Signal Transduction; Tetradecanoylphorbol Acetate - pharmacology; Heart; Signal transduction; Fibroblast growth factor; Vertebrata; Mammalia; Endothelin; Rat; Enzyme; Kinase; Rodentia; Myocyte
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1016/s0021-9258(17)42228-9

Maximally effective concentrations of endothelin-1 (ET-1), acidic FGF (aFGF), or 12-O-tetradecanoylphorbol-13-acetate (TPA) activated mitogen-activated protein kinase (MAPK) by 3-4-fold in crude extracts of myocytes cultured from neonatal rat heart ventricles. Maximal activation was achieved after 5 min. Thereafter, MAPK activity stimulated by ET-1 or aFGF declined to control values within 1-2 h, whereas activation by TPA was more sustained. Two peaks of MAPK activity (a 42- and a 44-kDa MAPK) were resolved in cells exposed to ET-1 or aFGF by fast protein liquid chromatography on a Mono Q column. One major and one minor peak of MAPK kinase (MAPKK) was stimulated by ET-1 or aFGF. Cardiac myocytes expressed protein kinase C (PKC)-alpha, -delta, -epsilon and -zeta as shown immunoblotting. Exposure to 1 microM TPA for 24 h down-regulated PKC-alpha, -delta, and -epsilon, but not PKC-zeta. This maneuver wholly abolished the activation of MAPK on re-exposure to TPA but did not affect the response to aFGF. The effect of ET-1 was partially down-regulated. ET-1 stimulated phospho[3H]inositide hydrolysis 18-fold, whereas aFGF stimulated by only 30%. Agonists which initially utilize dissimilar signaling pathways may therefore converge at the level of MAPKK/MAPK and this may be relevant to the hypertrophic response of the heart.