Mesalamine Restores Angiogenic Balance in Experimental Ulcerative Colitis by Reducing Expression of Endostatin and Angiostatin: Novel Molecular Mechanism for Therapeutic Action of Mesalamine

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 ␣ (TNF-␣), and matrix metalloproteinases (MMPs) 2 and 9 was determined by Western blots, enzymelinked immunosorbent assay, and zymography in the distal colon. 5-ASA treatment reduced lethargy and diarrhea and significantly decreased colonic lesions (by ϳ50%) compared with saline treatment in UC (both, P Ͻ 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 Ͻ 0.05). Furthermore, 5-ASA treatment significantly diminished increased activity of TNF-␣ 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 TNF␣. The inhibition of antiangiogenic factors may represent a novel molecular mechanism of the therapeutic action of 5-ASA.

Inappropriate Angiogenic Response as a Novel Mechanism of Duodenal Ulceration and Impaired Healing

“…In this study we demonstrated a concurrent increase of angiogenic VEGF and anti-angiogenic endostatin and angiostatin in the duodenal mucosa during chemically induced duodenal ulceration, indicating, for the first time, an altered balance between pro-and anti-angiogenic factors in duodenal ulceration. We also detected a similar interaction between angiogenic and anti-angiogenic factors in rats with experimental ulcerative colitis [27,28]. These unexpected findings may actually explain, for the first time, the initially surprising results demonstrating increased levels of angiogenic growth factors (e.g., bFGF, PDGF, VEGF) in the early stages of experimental duodenal ulceration.…”

Pretreatment with the probiotic VSL#3 delays transition from inflammation to dysplasia in a rat model of colitis-associated cancer

“…Proteins were extracted using lysis buffer and analyzed by Western blots (9). Lysates (100 g) were separated (15% SDS-PAGE) and blotted to polyvinylidene difluoride.…”

Antagonism of Protease-Activated Receptor 2 Protects against Experimental Colitis

“…On day 0, rats were weighed, given respective treatments of either sulfasalazine (100 mg/kg in olive oil p.o.) (Deng et al, 2009), GB88 (10 mg/kg in olive oil), or vehicle (500 l olive oil p.o. ), and fasted for 24 h with water supplied ad libitum.…”