RRC ID 42142
Author Tarnawski AS, Chai J, Pai R, Chiou SK.
Title Rebamipide activates genes encoding angiogenic growth factors and Cox2 and stimulates angiogenesis: a key to its ulcer healing action?
Journal Dig. Dis. Sci.
Abstract Clinical and experimental data indicate that rebamipide accelerates ulcer healing, improves scar quality, and prevents ulcer recurrence. However, the mechanisms responsible for these rebamipides' actions are not fully elucidated. We studied, using gene expression microarray analysis, which of the ulcer healing genes are activated by rebamipide treatment. Normal rat gastric epithelial cells (RGM1) were treated with either vehicle or rebamipide. Gene expression was determined using Affymetrix rat genome U34A gene chip arrays and data were analyzed using the GeneSpring program. Activation of some of the genes and protein translation were also examined by RT/PCR and Western blotting. Rebamipide significantly upregulated the proangiogenic genes encoding vascular endothelial growth factor (VEGF), by 7.5-fold, heparin binding epidermal growth-like factor (HB-EGF), by approximately 5-fold, fibroblast growth factor receptor-2 (FGFR2), by 4.4-fold, and cyclooxygenase-2 (Cox2), by 9.3-fold, as well as growth promoting genes, e.g., insulin growth factor-1 (IGF-1), by 5-fold. RT/PCR and Western blotting demonstrated that Cox2 mRNA and protein were upregulated; the latter, approximately 6-fold. Treatment of rat gastric mucosal endothelial cells with rebamipide stimulated in vitro angiogenesis by approximately 240% (vs. controls, P < 0.001). Conclusions are as follows. (1) Rebamipide activates in gastric epithelial RGM-1 cells a genetic program that promotes angiogenesis and signals cell growth and tissue regeneration. (2) In addition, rebamipide treatment directly stimulates angiogenesis in gastric microvascular endothelial cells. Thus rebamipide has two separate and distinct mechanisms of proangiogenic action: one through activation in gastric epithelial cells of proangiogenic growth factor genes and the second a direct angiogenic action on microvascular endothelial cells.
Volume 49(2)
Pages 202-9
Published 2004-2
DOI 10.1023/b:ddas.0000017439.60943.5c
PMID 15104358
MeSH Alanine / analogs & derivatives* Alanine / pharmacology* Animals Anti-Ulcer Agents / pharmacology* Cell Differentiation / genetics Cell Division / genetics Cell Line Cell Survival / drug effects Cyclooxygenase 2 Endothelium, Vascular / cytology Endothelium, Vascular / physiology Gastric Mucosa / cytology Gastric Mucosa / physiology Gene Expression Regulation / drug effects* Growth Substances / genetics* Isoenzymes / genetics* Isoenzymes / metabolism Microcirculation Neovascularization, Physiologic / drug effects* Neovascularization, Physiologic / physiology* Prostaglandin-Endoperoxide Synthases / genetics* Prostaglandin-Endoperoxide Synthases / metabolism Quinolones / pharmacology* RNA, Messenger / metabolism Rats Stomach / blood supply
IF 2.819
Times Cited 38
Human and Animal Cells