Role of anti-angiogenic factor endostatin in the pathogenesis of experimental ulcerative colitis

LIFE SCIENCES

卷:88

Article

Tolstanova, Ganna²  Deng, Xiaoming^2,3,4  Khomenko, Tetyana^2,3,4  Garg, Pallavi⁶  Paunovic, Brankica²  Chen, Longchuan²  Sitaraman, Shanthi V.⁶  Shiloach, Joseph⁷  Szabo, Sandor^2,3,4  Sandor, Zsuzsanna^1,5 

[1] Vet Adm Med Ctr, Med Hlth Care Grp, Long Beach, CA 90822 USA

[2] Vet Adm Med Ctr, Hlth Care Grp, Long Beach, CA 90822 USA

[3] Univ Calif Irvine, Dept Pathol, Irvine, CA 92717 USA

[4] Univ Calif Irvine, Dept Pharmacol, Irvine, CA 92717 USA

[5] Univ Calif Irvine, Dept Med, Irvine, CA 92717 USA

[6] Emory Univ, Atlanta, GA 30322 USA

[7] NIDDK, Biotechnol Core Lab, NIH, Bethesda, MD USA

关键词: Endostatin;    Matrix metalloproteinase-9;    VEGF;    Ulcerative colitis;   

DOI  :  10.1016/j.lfs.2010.10.026

来源: Elsevier

【 摘 要 】

Aims: Vascular endothelial growth factor (VEGF) and pathologic angiogenesis have been demonstrated to play a pathogenic role in the development and progression of inflammatory bowel disease. Thus, we hypothesized that the potent anti-angiogenic factor endostatin might play a beneficial role in experimental ulcerative colitis (UC). Main methods: We used three animal models of UC: (1) induced by 6% iodoacetamide (IA) in rats, or (2) by 3% dextran sulfate sodium (DSS) in matrix metalloproteinase-9 (MMP-9) knockout (KO) and wild-type mice, and (3) interleukin-10 (IL-10) KO mice. Groups of MMP-9 KO mice with DSS-induced UC were treated with endostatin or water for 5 days. Key findings: We found concomitant upregulation of VEGF, PDGF, MMP-9 and endostatin in both rat and mouse models of UC. A positive correlation between the levels of endostatin or VEGF and the sizes of colonic lesions was seen in IA-induced UC. The levels and activities of MMP-9 were also significantly increased during UC induced by IA and IL-10 KO. Deletion of MMP-9 decreased the levels of endostatin in both water- and DSS-treated MMP-9 KO mice. Treatment with endostatin significantly improved DSS-induced UC in MMP-9 KO mice. Significance: 1) Concomitantly increased endostatin is a defensive response to the increased VEGF in UC, 2) MMP-9 is a key enzyme to generate endostatin which may modulate the balance between VEGF and endostatin during experimental UC, and 3) endostatin treatment plays a beneficial role in UC. Thus, antiangiogenesis seems to be a new therapeutic option for UC. Published by Elsevier Inc.

【 授权许可】

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