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The role of the Grb2–p38 MAPK signaling pathway in cardiac hypertrophy and fibrosis
Shaosong Zhang, … , Yibin Wang, Anthony J. Muslin
Shaosong Zhang, … , Yibin Wang, Anthony J. Muslin
Published March 15, 2003
Citation Information: J Clin Invest. 2003;111(6):833-841. https://doi.org/10.1172/JCI16290.
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Article Cardiology Article has an altmetric score of 3

The role of the Grb2–p38 MAPK signaling pathway in cardiac hypertrophy and fibrosis

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Abstract

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 p38α (DN-p38α) and p38β (DN-p38β) MAPK were examined. DN-p38α and DN-p38β 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.

Authors

Shaosong Zhang, Carla Weinheimer, Michael Courtois, Attila Kovacs, Cindy E. Zhang, Alec M. Cheng, Yibin Wang, Anthony J. Muslin

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Figure 5

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Biochemical characterization of DN-p38α and DN-p38β transgenic mice. (a)...
Biochemical characterization of DN-p38α and DN-p38β transgenic mice. (a) Analysis of DN-p38α and DN-p38β MAPK protein levels in cardiac tissue from transgenic mice. Ventricular protein lysates obtained from DN-p38α mice, DN-p38β mice, and nontransgenic Swiss Black mice were separated by SDS-PAGE and examined by immunoblotting. Upper panel, isoform-specific anti–p38α MAPK immunoblot. Middle panel, isoform-specific anti–p38β MAPK immunoblot. Lower panel, anti-ERK immunoblot to control for protein loading. (b) Reduced p38α MAPK activity in DN-p38α transgenic mice. Ventricular protein lysates were generated 7 days after TAC or sham operation in DN-p38α transgenic mice or nontransgenic Swiss Black mice (NTG). Upper panel, anti-phospho–p38 MAPK immunoprecipitates were analyzed by isoform-specific anti–p38α MAPK immunoblotting. Middle panel, ventricular lysates were analyzed by anti-ERK immunoblotting to control for protein content. Lower panel, quantification of p38α MAPK protein levels in ventricular lysates by densitometric analysis of immunoreactive bands. Data are from three experiments. (c) Reduced p38β MAPK activity in DN-p38β transgenic mice. Upper panel, anti-phospho–p38 MAPK immunoprecipitates were analyzed by isoform-specific anti–p38β MAPK immunoblotting. Middle panel, ventricular lysates were analyzed by anti-ERK immunoblotting to control for protein content. Lower panel, quantification of p38β MAPK protein levels by densitometric analysis of immunoreactive bands. Data are from three experiments.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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