The role of the Grb2–p38 MAPK signaling pathway in cardiac hypertrophy and fibrosis
AUTOR(ES)
Zhang, Shaosong
FONTE
American Society for Clinical Investigation
RESUMO
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.
ACESSO AO ARTIGO
http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=153766Documentos Relacionados
- A novel angiotensin II type 2 receptor signaling pathway: possible role in cardiac hypertrophy
- Role of FAK signaling in chagasic cardiac hypertrophy
- The MEK1–ERK1/2 signaling pathway promotes compensated cardiac hypertrophy in transgenic mice
- Differential effects of ERK and p38 signaling in BMP-2 stimulated hypertrophy of cultured chick sternal chondrocytes
- Role of IRS-1-GRB-2 complexes in insulin signaling.