Molecular aspects of mechanical stress-induced cardiac hypertrophy.
To elucidate the signal transduction pathway from external stimuli to nuclear gene expression in mechanical stress-induced cardiac hypertrophy, we examined the time course of activation of protein kinases such as Raf-1 kinase (Raf-1), mitogen-activated protein kinase kinase (MAPKK), MAP kinases (MAPKs) and 90-kDa ribosomal S6 kinase (p90rsk) in neonatal rat cardiomyocytes. Mechanical stretch rapidly activated Raf-1 and its maximal activation was observed at 1-2 min after stretch. The activity of MAPKK was also increased by stretch, with a peak at 5 min after stretch. In addition, MAPKs and p90rsk were maximally activated at 8 min and at 10-30 min after stretch, respectively. Next, the relationship between mechanical stress-induced hypertrophy and the cardiac renin-angiotensin system was investigated. When the stretch-conditioned culture medium was transferred to the culture dish of non-stretched cardiac myocytes, the medium activated MAPK activity slightly but significantly, and the activation was completely blocked by the type 1 angiotensin II receptor antagonist, CV-11974. However, activation of Raf-1 and MAPKs provoked by stretching cardiomyocytes was only partially suppressed by pretreatment with CV-11974. These results suggest that mechanical stress activates the protein kinase cascade of phosphorylation in cardiac myocytes in the order of Raf-1, MAPKK, MAPKs and p90rsk, and that angiotensin II, which is secreted from stretched myocytes, activates a part of these protein kinases.
Yamazaki
T
T
Third Department of Internal Medicine, Faculty of Medicine, University of Tokyo, Japan.
Komuro
I
I
Yazaki
Y
Y
D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology; D001713:Biphenyl Compounds; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D006332:Cardiomegaly / Q000201:enzymology / Q000503:physiopathology*; D002478:Cells, Cultured; D004789:Enzyme Activation; D007093:Imidazoles / Q000494:pharmacology; D020929:Mitogen-Activated Protein Kinase Kinases; D008970:Molecular Weight; D004676:Myelin Basic Protein / Q000378:metabolism; D011494:Protein Kinases / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D019908:Proto-Oncogene Proteins c-raf; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D019893:Ribosomal Protein S6 Kinases; D015398:Signal Transduction; D013314:Stress, Mechanical; D013777:Tetrazoles / Q000494:pharmacology
D001562:Benzimidazoles; D001713:Biphenyl Compounds; D007093:Imidazoles; D004676:Myelin Basic Protein; D011518:Proto-Oncogene Proteins; D011725:Pyridines; D013777:Tetrazoles; C073402:PD 123319; D011494:Protein Kinases; D017346:Protein Serine-Threonine Kinases; D019908:Proto-Oncogene Proteins c-raf; D019893:Ribosomal Protein S6 Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D020929:Mitogen-Activated Protein Kinase Kinases; C081643:candesartan