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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2004;24:1384.)
© 2004 American Heart Association, Inc.

Vascular Biology

Basic Fibroblast Growth Factor Antagonizes Transforming Growth Factor-ß1–Induced Smooth Muscle Gene Expression Through Extracellular Signal–Regulated Kinase 1/2 Signaling Pathway Activation

Keiko Kawai-Kowase; Hiroko Sato; Yuko Oyama; Hiroyoshi Kanai; Mahito Sato; Hiroshi Doi; Masahiko Kurabayashi

From the Department of Medicine and Biological Science, Gunma University Graduate School of Medicine, Gunma, Japan.

Correspondence to Masahiko Kurabayashi, MD, PhD, Department of Medicine and Biological Science, Gunma University Graduate School of Medicine, 3-39-15 Showa-machi, Maebashi, Gunma 371-8511, Japan. E-mail mkuraba{at}med.gunma-u.ac.jp

Objective— Transforming growth factor-ß1 (TGFß1) and fibroblast growth factor (FGF) families play a pivotal role during vascular development and in the pathogenesis of vascular disease. However, the interaction of intracellular signaling evoked by each of these growth factors is not well understood. The present study was undertaken to examine the molecular mechanisms that mediate the effects of TGFß1 and basic FGF (bFGF) on smooth muscle cell (SMC) gene expression.

Methods and Results— TGFß1 induction of SMC gene expression, including smooth muscle protein 22- (SM22) and smooth muscle -actin, was examined in the pluripotent 10T1/2 cells. Marked increase in these mRNA levels by TGFß1 was inhibited by c-Src-tyrosine kinase inhibitors and protein synthesis inhibitor cycloheximide. Functional studies with deletion and site-directed mutation analysis of the SM22 promoter demonstrated that TGFß1 activated the SM22 promoter through a CC(A/T-rich)₆GG (CArG) box, which serves as a serum response factor (SRF)–binding site. TGFß1 increased SRF expression through an increase in transcription of the SRF gene. In the presence of bFGF, TGFß1 induction of SMC marker gene expression was significantly attenuated. Transient transfection assays showed that bFGF significantly suppressed induction of the SM22 promoter–driven luciferase activity by TGFß1, whereas bFGF had no effects on the TGFß1-mediated increase in SRF expression and SRF:DNA binding activity. Mitogen-activated protein kinase kinase-1 (MEK1) inhibitor PD98059 abrogated the bFGF-mediated suppression of TGFß1-induced SMC gene expression.

Conclusion— Our data suggest that bFGF-induced MEK/extracellular signal-regulated kinase signaling plays an antagonistic role in TGFß1-induced SMC gene expression through suppression of the SRF function. These data indicate that opposing effects of bFGF and TGFß1 on SMC gene expression control the phenotypic plasticity of SMCs.

TGFß1 induces SMC gene expression through an increase in SRF gene expression, which activates CArG-dependent transcription, and Src-tyrosine kinase is required for such an induction in 10T1/2 cells and vascular SMC. bFGF antagonizes TGFß1-induced SMC gene expression, although MEK1 activation without interfering with SRF:DNA binding activity and SRF gene expression.

Key Words: basic fibroblast growth factor • transforming growth factor-ß1 • serum response factor • SM22 • smooth muscle cells

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