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

Publication ,  Journal Article
Zhang, S; Weinheimer, C; Courtois, M; Kovacs, A; Zhang, CE; Cheng, AM; Wang, Y; Muslin, AJ
Published in: J Clin Invest
March 2003

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.

Duke Scholars

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Published In

J Clin Invest

DOI

ISSN

0021-9738

Publication Date

March 2003

Volume

111

Issue

6

Start / End Page

833 / 841

Location

United States

Related Subject Headings

  • p38 Mitogen-Activated Protein Kinases
  • Proteins
  • Protein-Tyrosine Kinases
  • Myocardium
  • Mitogen-Activated Protein Kinases
  • Mice
  • MAP Kinase Signaling System
  • Immunology
  • GRB2 Adaptor Protein
  • Focal Adhesion Protein-Tyrosine Kinases
 

Citation

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Zhang, S., Weinheimer, C., Courtois, M., Kovacs, A., Zhang, C. E., Cheng, A. M., … Muslin, A. J. (2003). The role of the Grb2-p38 MAPK signaling pathway in cardiac hypertrophy and fibrosis. J Clin Invest, 111(6), 833–841. https://doi.org/10.1172/JCI16290
Zhang, Shaosong, Carla Weinheimer, Michael Courtois, Attila Kovacs, Cindy E. Zhang, Alec M. Cheng, Yibin Wang, and Anthony J. Muslin. “The role of the Grb2-p38 MAPK signaling pathway in cardiac hypertrophy and fibrosis.J Clin Invest 111, no. 6 (March 2003): 833–41. https://doi.org/10.1172/JCI16290.
Zhang S, Weinheimer C, Courtois M, Kovacs A, Zhang CE, Cheng AM, et al. The role of the Grb2-p38 MAPK signaling pathway in cardiac hypertrophy and fibrosis. J Clin Invest. 2003 Mar;111(6):833–41.
Zhang, Shaosong, et al. “The role of the Grb2-p38 MAPK signaling pathway in cardiac hypertrophy and fibrosis.J Clin Invest, vol. 111, no. 6, Mar. 2003, pp. 833–41. Pubmed, doi:10.1172/JCI16290.
Zhang S, Weinheimer C, Courtois M, Kovacs A, Zhang CE, Cheng AM, Wang Y, Muslin AJ. The role of the Grb2-p38 MAPK signaling pathway in cardiac hypertrophy and fibrosis. J Clin Invest. 2003 Mar;111(6):833–841.

Published In

J Clin Invest

DOI

ISSN

0021-9738

Publication Date

March 2003

Volume

111

Issue

6

Start / End Page

833 / 841

Location

United States

Related Subject Headings

  • p38 Mitogen-Activated Protein Kinases
  • Proteins
  • Protein-Tyrosine Kinases
  • Myocardium
  • Mitogen-Activated Protein Kinases
  • Mice
  • MAP Kinase Signaling System
  • Immunology
  • GRB2 Adaptor Protein
  • Focal Adhesion Protein-Tyrosine Kinases