p38 MAP-kinase in cultured adult rat ventricular cardiomyocytes: expression and involvement in hypertrophic signalling.
Both alpha-adrenoceptor- and beta-adrenoceptor-stimulation lead to hypertrophic growth of the myocardium. But only beta-adrenoceptor-stimulation requires the pre-cultivation of cells with active TGF-beta. In order to define signalling molecules that are specifically involved in beta-adrenoceptor-dependent hypertrophy, changes in expression and hypertrophic responsiveness during pre-cultivation with TGF-beta were investigated. Isolated adult ventricular cardiomyocytes from rats were either cultured in 20% (v/v) foetal calf serum (FCS) to activate autocrine released TGF-beta or used without pre-treatment. Protein synthesis was analysed by (14)C-phenylalanine incorporation. Expression of signalling molecules was determined by immunoblotting. During cultivation of cardiomyocytes with active TGF-beta only the expression of p38 MAP-kinase increased. Subsequent stimulation of beta-adrenoceptors induced protein synthesis in a p38 MAP-kinase-dependent way. However, stimulation of beta-adrenoceptors activated p38 MAP-kinase irrespective of pre-treatment with TGF-beta. In the absence of this cytokine, hyperosmolarity or reconstitution of mechanical activity increased protein synthesis via p38 MAP-kinase activation in freshly isolated cells. In conclusion, activation of p38 MAP-kinase is a newly identified necessary signalling step required for beta-adrenoceptor induced hypertrophic growth. Like activation of adenyl cyclase, activation of p38 MAP-kinase is up-stream of the TGF-beta-induced coupling to the regulation of protein synthesis. Reconstitution of mechanical activity mimics the co-activation required and induced by TGF-beta.
Wenzel
Sibylle
S
Physiologisches Institut, Justus-Liebig-Universität, Aulweg 129, D-35392 Giessen, Germany. Sibylle.Wenzel@physiologie.med.uni-giessen.de
Müller
Claudia
C
Piper
Hans Michael
HM
Schlüter
Klaus-Dieter
KD
D000818:Animals; D006332:Cardiomegaly / Q000503:physiopathology*; D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000502:physiology; D007093:Imidazoles / Q000494:pharmacology; D008297:Male; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D011943:Receptors, Adrenergic, beta / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology*; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
D004791:Enzyme Inhibitors; D007093:Imidazoles; D011725:Pyridines; D011943:Receptors, Adrenergic, beta; D016212:Transforming Growth Factor beta; D048051:p38 Mitogen-Activated Protein Kinases; C090942:4-(4-fluorophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)imidazole