The role of the Grb2-p38 MAPK signaling pathway in cardiac hypertrophy and fibrosis.
Cardiac hypertrophy is a common response to pressure overload and is associated with increased mortality. Mechanical stress in the heart can result in the integrin-mediated activation of focal adhesion kinase and the subsequent recruitment of the Grb2 adapter molecule. Grb2, in turn, can activate MAPK cascades via an interaction with the Ras guanine nucleotide exchange factor SOS and with other signaling intermediates. We analyzed the role of the Grb2 adapter protein and p38 MAPK in cardiac hypertrophy. Mice with haploinsufficiency of the Grb2 gene (Grb2(+/-) mice) appear normal at birth but have defective T cell signaling. In response to pressure overload, cardiac p38 MAPK and JNK activation was inhibited and cardiac hypertrophy and fibrosis was blocked in Grb2(+/-) mice. Next, transgenic mice with cardiac-specific expression of dominant negative forms of p38alpha (DN-p38alpha) and p38beta (DN-p38beta) MAPK were examined. DN-p38alpha and DN-p38beta mice developed cardiac hypertrophy but were resistant to cardiac fibrosis in response to pressure overload. These results establish that Grb2 action is essential for cardiac hypertrophy and fibrosis in response to pressure overload, and that different signaling pathways downstream of Grb2 regulate fibrosis, fetal gene induction, and cardiomyocyte growth.
Zhang
Shaosong
S
Center for Cardiovascular Research, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
Weinheimer
Carla
C
Courtois
Michael
M
Kovacs
Attila
A
Zhang
Cindy E
CE
Cheng
Alec M
AM
Wang
Yibin
Y
Muslin
Anthony J
AJ
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D001794:Blood Pressure; D006332:Cardiomegaly / Q000209:etiology*; D005355:Fibrosis; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; D051380:GRB2 Adaptor Protein; D020935:MAP Kinase Signaling System / Q000502:physiology; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000502:physiology*; D009206:Myocardium / Q000473:pathology*; D011505:Protein-Tyrosine Kinases / Q000502:physiology; D011506:Proteins / Q000502:physiology*; D048051:p38 Mitogen-Activated Protein Kinases
D048868:Adaptor Proteins, Signal Transducing; D051380:GRB2 Adaptor Protein; C495949:Grb2 protein, mouse; D011506:Proteins; D011505:Protein-Tyrosine Kinases; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; C496051:Ptk2 protein, mouse; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases