Grb2 haploinsufficiency in mice almost completely blocked cardiac hypertrophy and fibrosis in response to pressure overload, whereas dominant negative p38 MAPK expression blocked fibrosis but not hypertrophy.
Does Grb2 haploinsufficiency or dominant negative p38 MAPK expression prevent cardiac hypertrophy and fibrosis in response to pressure overload in mice?
Grb2 is essential for cardiac hypertrophy and fibrosis in response to pressure overload, while downstream p38 MAPK pathways specifically regulate fibrosis rather than cardiomyocyte growth.
Absolute Event Rate: 3.7% vs 4.6%
p-value: p=<0.01
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.
Zhang et al. (Sat,) conducted a other in Cardiac hypertrophy and fibrosis. Grb2 haploinsufficiency (Grb2+/-) vs. Wild-type (Grb2+/+) mice was evaluated on Left ventricular weight to body weight ratio (LVW/BW) 7 days after transverse aortic constriction (p=<0.01). Grb2 haploinsufficiency in mice almost completely blocked cardiac hypertrophy and fibrosis in response to pressure overload, whereas dominant negative p38 MAPK expression blocked fibrosis but not hypertrophy.