Reduction of angiotensin II-induced activation of mitogen-activated protein kinase in cardiac hypertrophy.
Mitogen-activated protein (MAP) kinases play a role in cell growth and are activated in the heart by cardiac stretch and various growth factors, but their role in signal transduction pathways once the heart has undergone hypertrophy is uncertain. To investigate the regulation of MAP kinases in the heart in response to angiotensin II (ang II), once cardiac hypertrophy has become established, ventricular and skeletal muscle explants were studied from Dahl S salt-sensitive and Dahl R salt-resistant rats that were on a high (6% NaCl) salt supplement in their diet. Cardiac hypertrophy was produced in the Dahl S but not R rat through NaCl-induced hypertension. MAP kinases were assayed by myelin protein phosphotransferase activity in MonoQ fractions of cell extracts. Ang II increased MAP kinases mainly in extracts from nonhypertrophic ventricles of Dahl R rats on a high-salt diet. Immunoblots revealed predominantly p44ERK1 with lower amounts p42MAPK in rat ventricle, and no apparent changes with hypertrophy. In hypertrophied hearts, ang II-induced MAP kinase activity was less markedly increased and more rapidly fell to baseline levels in comparison to the response in nonhypertrophied hearts. Prolonged ang II exposure did not produce the same effect on MAP kinase activity in ventricles from Dahl S rats on a low-salt diet, or skeletal muscle from salt-fed Dahl R and S rats. The ability of phorbol myristate acetate to simulate MAP kinase and ang II to simulate translocation of protein kinase C from the cytosole to the membrane was similarly compromised in hypertrophied ventricles. These results are consistent with a disturbance in the regulation of cell-signalling pathways in cardiac hypertrophy in which the MAP kinase response to ang II is dramatically altered.
Rabkin
S W
SW
Department of Medicine, University of British Columbia, Vancouver, Canada. rabkin@unixg.ubc.ca
Sunga
P S
PS
Sanghera
J S
JS
Pelech
S L
SL
D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism*; D006332:Cardiomegaly / Q000201:enzymology*; D002451:Cell Compartmentation; D004789:Enzyme Activation / Q000187:drug effects; D018482:Muscle, Skeletal / Q000201:enzymology; D011493:Protein Kinase C / Q000378:metabolism; D051381:Rats; D011922:Rats, Mutant Strains; D015398:Signal Transduction; D017673:Sodium Chloride, Dietary
D017673:Sodium Chloride, Dietary; D000804:Angiotensin II; D011493:Protein Kinase C; D017871:Calcium-Calmodulin-Dependent Protein Kinases