Reactive oxygen species in mechanical stress-induced cardiac hypertrophy.
Mechanical stress induces various hypertrophic responses including activation of mitogen-activated protein kinases (MAPKs) in cardiac myocytes. Here we examined the role of the small GTP-binding proteins of Rho family and reactive oxygen species (ROS) in stretch-induced activation of p38MAPK in cardiomyocytes. Overexpression of dominant-negative mutants of Rac1 (D.N. Rac1), D.N.RhoA and D.N.Cdc42 suppressed stretch-induced activation of p38MAPK. Overexpression of constitutively active mutants of Rac1 (C.A.Rac1) and C.A.Cdc42 increased the p38MAPK activity in the absence of mechanical stress. Pretreatment with N-acetyl-L-cysteine and N-(2-mercaptopropionyl)-glycine (NAC) suppressed stretch-induced activation of p38MAPK. Mechanical stretch increased intracellular ROS generation, which was abrogated by overexpression of D.N.Rac1 and attenuated by overexpression of D.N.RhoA and D.N.Cdc42. An increase in protein synthesis evoked by mechanical stretch was suppressed by overexpression of D.N.Rac1 and pretreatment with NAC. These results suggest that mechanical stress induces cardiac hypertrophy through the Rac1-ROS-p38MAPK pathway in cardiac myocytes.
Aikawa
R
R
Department of Cardiovascular Medicine, University of Tokyo Graduate School of Medicine, Tokyo, Japan.
Nagai
T
T
Tanaka
M
M
Zou
Y
Y
Ishihara
T
T
Takano
H
H
Hasegawa
H
H
Akazawa
H
H
Mizukami
M
M
Nagai
R
R
Komuro
I
I
D000818:Animals; D006332:Cardiomegaly / Q000209:etiology* / Q000378:metabolism* / Q000473:pathology; D002478:Cells, Cultured; D004789:Enzyme Activation; D015870:Gene Expression; D018390:Gene Targeting; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009154:Mutation; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism*; D013314:Stress, Mechanical; D020764:cdc42 GTP-Binding Protein / Q000235:genetics; D048051:p38 Mitogen-Activated Protein Kinases; D020830:rac1 GTP-Binding Protein / Q000235:genetics; D020742:rhoA GTP-Binding Protein / Q000235:genetics
D017382:Reactive Oxygen Species; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D020764:cdc42 GTP-Binding Protein; D020830:rac1 GTP-Binding Protein; D020742:rhoA GTP-Binding Protein