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TNF‐α induces MMP‐9 expression via a TNFR1/c‐Src/EGFR, PDGFR‐dependent pathway in rat cardiomyoblastic cells
Author(s) -
Hsu Ru-Chun,
Yang Chuen-Mao
Publication year - 2012
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.26.1_supplement.1114.2
Subject(s) - matrix metalloproteinase , tumor necrosis factor alpha , mapk/erk pathway , protein kinase b , ly294002 , pi3k/akt/mtor pathway , p38 mitogen activated protein kinases , chemistry , cancer research , phosphorylation , microbiology and biotechnology , signal transduction , proto oncogene tyrosine protein kinase src , endocrinology , biology , biochemistry
Increased release of tumor necrosis factor alpha (TNF‐α) causes myocardial remodeling and progression of congestive heart failure (CHF). And TNF receptor activates proteolytic system, the matrix metalloproteinases (MMPs), especially MMP‐9, to degrade extracellular components in myocardial remodeling. Therefore, TNF‐α‐inducible matrix metalloproteinase‐9 (MMP‐9) may play a critical role in adverse heart remodeling. However, the molecular mechanisms of TNF‐α‐induced MMP‐9 expression in rat cardiomyoblasts (H9c2) which contributes to cardiac remodeling are largely unknown. Here, we showed that TNF‐α induced MMP‐9 expression and mRNA levels in a time‐dependent manner. This response was attenuated by pretreatment with an anti‐TNFR1 antibody and the inhibitors of MEK1/2 (U0126), JNK1/2 (SP600125), p38 MAPK (SB202190), c‐Src (PP1), EGFR (AG1478), PDGFR (AG1296), PI3K (LY294002), Akt (SH‐5), NADPH oxidase (apocynin and DPI), and NF‐κB (Bay11‐7082). Moreover, TNF‐α‐stimulated ERK1/2 or p38 MAPK phosphorylation and NF‐κB (p65) nuclear translocation were attenuated by pretreatment with AG1478, AG1296, or PP1. Taken together, these results suggest that in H9c2 cells, TNF‐α might activate TNF receptor coupling to transactivate RTK and MAPKs pathways, leading to NF‐κB (p65) nuclear translocation to up‐regulate MMP‐9 expression.