Hypoxia induces discoidin domain receptor-2 expression via the p38 pathway in vascular smooth muscle cells to increase their migration

Shih-Chung Chen; Bao-Wei Wang; Danny Ling Wang; Kou-Gi Shyu

doi:10.1016/j.bbrc.2008.07.092

Hypoxia induces discoidin domain receptor-2 expression via the p38 pathway in vascular smooth muscle cells to increase their migration

Biochem Biophys Res Commun. 2008 Oct 3;374(4):662-7. doi: 10.1016/j.bbrc.2008.07.092. Epub 2008 Jul 26.

Authors

Shih-Chung Chen¹, Bao-Wei Wang, Danny Ling Wang, Kou-Gi Shyu

Affiliation

¹ Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, 250 Wu-Xin Street, Taipei 110, Taiwan.

PMID: 18664364
DOI: 10.1016/j.bbrc.2008.07.092

Abstract

Discoidin domain receptor-2 (DDR2) is a receptor tyrosine kinase that binds to the extracellular matrix. We investigated the role of hypoxia in DDR2 expression in vascular smooth muscle cells (VSMCs) and the underlying mechanism. Subjecting VSMCs to hypoxia (2.5% O(2)) induced DDR2 expression; treatments with a specific inhibitor (SB203580) of p38 mitogen-activated protein kinase (MAPK) or p38-specific small interference RNA (siRNA) abolished this hypoxia-induced DDR2 expression. Gel shifting assays showed that hypoxia increased the Myc-Max-DNA binding activity in the promoter region of DDR2; inhibition of p38 MAPK activation by SB203580 and p38-specific siRNA blocked hypoxia-induced DDR2 promoter activity. Hypoxia also induced matrix metalloproteinase-2 (MMP-2) activity in VSMCs and increased their migration. These VSMC responses to hypoxia were inhibited by DDR2- and p38-specific siRNAs. Our results suggested that hypoxia induces DDR2 expression in VSMCs at the transcriptional level, which is mediated by the p38 MAPK pathway and contributes to VSMC migration.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / metabolism
Cell Movement*
DNA / metabolism
Discoidin Domain Receptors
Electrophoretic Mobility Shift Assay
Hypoxia / enzymology*
Hypoxia / genetics
Imidazoles / pharmacology
Male
Muscle, Smooth, Vascular / enzymology
Muscle, Smooth, Vascular / physiology*
Myocytes, Smooth Muscle / enzymology
Myocytes, Smooth Muscle / physiology*
Promoter Regions, Genetic
Protein Kinase Inhibitors / pharmacology
Proto-Oncogene Proteins c-myc / metabolism
Pyridines / pharmacology
RNA, Small Interfering / genetics
Rats
Rats, Sprague-Dawley
Receptor Protein-Tyrosine Kinases / biosynthesis*
Receptor Protein-Tyrosine Kinases / genetics
Receptors, Mitogen / biosynthesis*
Receptors, Mitogen / genetics
p38 Mitogen-Activated Protein Kinases / genetics
p38 Mitogen-Activated Protein Kinases / metabolism*

Substances

Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
Imidazoles
Max protein, rat
Protein Kinase Inhibitors
Proto-Oncogene Proteins c-myc
Pyridines
RNA, Small Interfering
Receptors, Mitogen
DNA
Discoidin Domain Receptors
Receptor Protein-Tyrosine Kinases
p38 Mitogen-Activated Protein Kinases
SB 203580