Key result
Grb2 haploinsufficiency blocks pressure-induced hypertrophy and fibrosis in mice, while p38 MAPK inhibition prevents only fibrosis.
Why the study?
The role of the Grb2 adapter protein and p38 MAPK signaling pathway in cardiac hypertrophy and fibrosis in response to pressure overload was not fully understood.
Does the Grb2-p38 MAPK signaling pathway regulate cardiac hypertrophy and fibrosis in response to pressure overload in mice?
Does the Grb2-p38 MAPK signaling pathway regulate cardiac hypertrophy and fibrosis in response to pressure overload in mice?
Grb2 is essential for cardiac hypertrophy and fibrosis in response to pressure overload, with different downstream pathways regulating fibrosis versus cardiomyocyte growth.
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.
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Zhang et al. (2003) studied Cardiac hypertrophy and fibrosis. Grb2 haploinsufficiency and dominant negative p38 MAPK vs. Wild-type mice was evaluated on Cardiac hypertrophy and fibrosis in response to pressure overload. Grb2 haploinsufficiency blocked cardiac hypertrophy and fibrosis in response to pressure overload, whereas dominant negative p38 MAPK expression prevented fibrosis but not hypertrophy in mice.
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