title: Neurotensin Promotes the Development of Colitis and Intestinal Angiogenesis via Hif-1α-miR-210 Signaling.
abstract: Neurotensin (NT) via its receptor 1 (NTR1) modulates the development of colitis, decreases HIF-1α/PHD2 interaction, stabilizes and increases HIF-1α transcriptional activity, and promotes intestinal angiogenesis. HIF-1α induces miR-210 expression, whereas miR-210 is strongly upregulated in response to NT in NCM460 human colonic epithelial cells overexpressing NTR1 (NCM460-NTR1). In this study, we examined whether NT activates a NTR1-HIF-1α-miR-210 cascade using in vitro (NCM460-NTR1 cells) and in vivo (transgenic mice overexpressing [HIF-1α-OE] or lacking HIF-1α [HIF-1α-knockout (KO)] in intestinal epithelial cells and mice lacking NTR1 [NTR1-KO]) models. Pretreatment of NCM460-NTR1 cells with the HIF-1α inhibitor PX-478 or silencing of HIF-1α (small interfering HIF-1α) attenuated miR-210 expression in response to NT. Intracolonic 2,4,6-trinitrobenzenesulfonic acid (TNBS) administration (2-d model) increased colonic miR-210 expression that was significantly reduced in NTR1-KO, HIF-1α-KO mice, and wild-type mice pretreated intracolonically with locked nucleic acid anti-miR-210. In contrast, HIF-1α-OE mice showed increased miR-210 expression at baseline that was further increased following TNBS administration. HIF-1α-OE mice had also exacerbated TNBS-induced neovascularization compared with TNBS-exposed wild-type mice. TNBS-induced neovascularization was attenuated in HIF-1α-KO mice, or mice pretreated intracolonically with anti-miR-210. Intracolonic anti-miR-210 also reduced colitis in response to TNBS (2 d). Importantly, miR-210 expression was increased in tissue samples from ulcerative colitis patients. We conclude that NT exerts its proinflammatory and proangiogenic effects during acute colitis via a NTR1-prolyl hydroxylase 2/HIF-1α-miR-210 signaling pathway. Our results also demonstrate that miR-210 plays a proinflammatory role in the development of colitis.
authors.affiliation: Inflammatory Bowel Disease Center, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095;
authors.forename: Kyriaki
authors.identifier: 0000-0003-1535-2490
authors.initials: K
authors.lastname: Bakirtzi
authors.affiliation: Inflammatory Bowel Disease Center, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095;
authors.forename: Ivy Ka Man
authors.identifier: 0000-0002-7430-1215
authors.initials: IK
authors.lastname: Law
authors.affiliation: Division of Gastroenterology, Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI 48109;
authors.forename: Xiang
authors.identifier: 0000-0003-4704-1814
authors.initials: X
authors.lastname: Xue
authors.affiliation: Division of Digestive Diseases, Center for Systems Biomedicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095; and.
authors.forename: Dimitrios
authors.identifier: 0000-0002-6832-0786
authors.initials: D
authors.lastname: Iliopoulos
authors.affiliation: Division of Gastroenterology, Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI 48109; Division of Gastroenterology, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI 48109.
authors.forename: Yatrik M
authors.initials: YM
authors.lastname: Shah
authors.affiliation: Inflammatory Bowel Disease Center, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095; cpothoulakis@mednet.ucla.edu.
authors.forename: Charalabos
authors.initials: C
authors.lastname: Pothoulakis
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D003093:Colitis, Ulcerative / Q000378:metabolism*; D003106:Colon / Q000098:blood supply / Q000473:pathology; D004847:Epithelial Cells / Q000378:metabolism; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D007413:Intestinal Mucosa / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D035683:MicroRNAs / Q000378:metabolism*; D009150:Mustard Compounds / Q000008:administration & dosage; D016328:NF-kappa B / Q000378:metabolism; D009389:Neovascularization, Pathologic / Q000378:metabolism*; D009496:Neurotensin / Q000378:metabolism*; D010666:Phenylpropionates / Q000008:administration & dosage; D018028:Receptors, Neurotensin / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D014302:Trinitrobenzenesulfonic Acid; D015854:Up-Regulation / Q000187:drug effects
chemical_list: C492908:2-amino-3-(4'-N,N-bis(2-chloroethyl)amino)phenylpropionic acid N-oxide; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C543800:MIRN210 microRNA, human; D035683:MicroRNAs; D009150:Mustard Compounds; D016328:NF-kappa B; D010666:Phenylpropionates; D018028:Receptors, Neurotensin; C114036:neurotensin type 1 receptor; D009496:Neurotensin; D014302:Trinitrobenzenesulfonic Acid