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

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

Research output: Contribution to journalArticlepeer-review

170 Scopus citations


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-pβ) 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.

Original languageEnglish
Pages (from-to)833-841
Number of pages9
JournalJournal of Clinical Investigation
Issue number6
StatePublished - Mar 2003


Dive into the research topics of 'The role of the Grb2-p38 MAPK signaling pathway in cardiac hypertrophy and fibrosis'. Together they form a unique fingerprint.

Cite this