Abstract
Mesalamine (5-aminosalicylate acid, 5-ASA) is an effective treatment for ulcerative colitis (UC). The mechanisms of its actions are not fully understood. Because angiogenesis is critical for healing UC, we examined whether 5-ASA alters the angiogenic balance between angiogenic factors [e.g., vascular endothelial growth factor (VEGF)] and antiangiogenic factors (e.g., endostatin and angiostatin) in the colon in experimental UC. Rats were treated with saline or 5-ASA (100 mg/kg) twice daily and euthanized 3 or 7 days after iodoacetamide-induced UC. Clinical signs (e.g., lethargy, diarrhea) and UC lesions were measured. Expression of VEGF, endostatin, angiostatin, tissue necrosis factor α (TNF-α), and matrix metalloproteinases (MMPs) 2 and 9 was determined by Western blots, enzyme-linked immunosorbent assay, and zymography in the distal colon. 5-ASA treatment reduced lethargy and diarrhea and significantly decreased colonic lesions (by ∼50%) compared with saline treatment in UC (both, P < 0.05). 5-ASA did not reverse the increased levels of VEGF, but it significantly reduced expression of endostatin and angiostatin in UC compared with vehicle treatment (both, P < 0.05). Furthermore, 5-ASA treatment significantly diminished increased activity of TNF-α and MMP9 in UC. This is the first demonstration that 5-ASA treatment reverses an imbalance between the angiogenic factor VEGF and antiangiogenic factors endostatin and angiostatin in experimental UC. The effect of 5-ASA in UC may be caused by the down-regulation of expression of endostatin and angiostatin by modulation of MMP2 and MMP9 via inhibition of TNFα. The inhibition of antiangiogenic factors may represent a novel molecular mechanism of the therapeutic action of 5-ASA.
Footnotes
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This work was supported by Procter & Gamble Pharmaceuticals [Grant MIRB800] (to Z.S.).
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This work was previously presented in abstract and poster forms: Deng X, Tolstanova G, Khomenko T, Chen L, Xiong X, Tarnawski A, Szabo S, and Sandor Z (2008) Mesalamine restores angiogenic balance in experimental ulcerative colitis by reducing expression of endostatin and angiostatin: novel molecular mechanism for mesalamine's therapeutic action. Annual Conference of Digestive Disease Week 2008; 2008 May 19–24; San Diego, CA. American Gastroenterological Association, Bethesda, MD.
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
doi:10.1124/jpet.109.158022
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ABBREVIATIONS:
- VEGF
- vascular endothelial growth factor
- 5-ASA
- mesalamine; 5-aminosalicylate acid
- IA
- iodoacetamide
- UC
- ulcerative colitis
- MMP
- matrix metalloproteinase
- MC
- methylcellulose
- GAPDH
- glyceraldehyde-3-phosphate dehydrogenase
- TNF-α
- tissue necrosis factor α
- PPAR-γ
- peroxisome proliferator-activated receptor-γ
- ELISA
- enzyme-linked immunosorbent assay.
- Received June 22, 2009.
- Accepted September 16, 2009.
- © 2009 by The American Society for Pharmacology and Experimental Therapeutics
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