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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

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 1

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Biochemical characterization of Grb2 and MAPK in murine cardiac tissue 7...
Biochemical characterization of Grb2 and MAPK in murine cardiac tissue 7 days after TAC or sham operation. (a) Load-induced formation of a Grb2-FAK complex. Anti-FAK immunoprecipitates (IP) derived from ventricular lysates were separated by SDS-PAGE and analyzed by immunoblotting with an anti-Grb2 antibody (lower panel). Anti-FAK immunoprecipitates were also analyzed in parallel by immunoblotting with an anti-FAK antibody (upper panel). (b) Reduced Grb2 protein content in Grb2+/– cardiac tissue. Upper panel, ventricular lysates were analyzed by immunoblotting with an anti-Grb2 antibody. Lower panel, quantification of Grb2 protein levels by densitometric analysis of immunoreactive bands. (c) Analysis of p38 MAPK activation in Grb2+/– cardiac tissue. Ventricular lysates were analyzed by immunoblotting with an anti-phospho–p38 MAPK antibody (upper panel). Lysates were also analyzed in parallel by immunoblotting with an anti–p38 MAPK (lower panel) antibody to control for protein content. (d) Analysis of JNK activation in Grb2+/– cardiac tissue. Lysates were analyzed by immunoblotting with an anti–phospho-JNK antibody (upper panel). Lysates were also analyzed in parallel by immunoblotting with an anti-JNK (lower panel) antibody to control for protein content. (e) Analysis of ERK activity in Grb2+/– cardiac tissue. Anti-ERK immunoprecipitates derived from ventricular lysates were analyzed by in vitro kinase assay by use of Elk-1 protein as a substrate. Anti-phospho–Elk-1 antibody immunoblotting was performed to assess ERK activity (upper panel). Lysates were also analyzed in parallel by immunoblotting with an anti-ERK (lower panel) antibody to control for protein content. Sham, sham operation.
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