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Tumor necrosis factor‐alpha (TNF)‐mediated vascular smooth muscle cell (VSMC) proliferation is p38‐dependent
Author(s) -
Chen Chun Cheng Andy,
Young Wilson,
Lee Irene,
Ferreri Nicholas R
Publication year - 2007
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.21.5.a520-a
Subject(s) - tumor necrosis factor alpha , p38 mitogen activated protein kinases , vascular smooth muscle , mapk/erk pathway , phosphorylation , microbiology and biotechnology , chemistry , endocrinology , medicine , biology , smooth muscle
We hypothesized that TNF increases cyclooxygenase‐2 (COX‐2)‐dependent VSMC proliferation via activation of p38 MAPK. A transient increase in p38 MAPK phosphorylation (pp38) was observed after challenge with TNF (1 nM). In vitro kinase reactions, using a recombinant ATF‐2 fusion protein as substrate, verified that TNF increases p38 MAPK activity in VSMC. Increases in pp38 MAPK were absent in VSMC from TNFR1 deficient mice but present in cells from TNFR2 deficient mice, suggesting that induction of p38 MAPK activity was dependent on signaling via TNFR1. TNF‐mediated COX‐2 expression also was absent in VSMC from TNFR1 knockout mice. Moreover, COX‐2 expression increased in cells from TNFR2 deficient mice challenged with TNF, an effect blocked by pretreatment with a neutralizing anti‐TNFR1 antibody. Inhibition of p38 MAPK activity by SB203580 (5 μM) blocked TNF‐mediated COX‐2 expression and VSMC proliferation; SB239063 (5 μM) also blocked proliferation. The increase in VSMC proliferation in response to TNF was absent in cells from TNFR1 deficient mice but present in cells from TNFR2 deficient mice. Moreover, the proliferative response in cells from TNFR2 deficient mice was blocked by NS398 (0.1 μM) and anti‐TNFR1, suggesting that the response is both TNFR1‐ and COX‐2‐dependent. Targeting the p38 MAPK pathway may be beneficial in cardiovascular diseases associated with abnormal VSMC growth.