title: Altered Expression of Angiotensinogen and Mediators of Angiogenesis in Ileal Crohn's Disease.
abstract: OBJECTIVE
  Angiotensin II (AII) is a powerful splanchnic vasoconstrictor with pro-inflammatory and pro-fibrotic properties. Angiotensin converting enzyme (ACE) inhibitors and AII Receptor Antagonists (ARBs) are therapeutic in animal models of colitis. The aim of this case-control study is to determine the expression of angiotensinogen and related genes in human ileal Crohn's disease.
  
  
  METHODS
  Using quantitative real-time polymerase chain reaction (RT-PCR), we measured mRNA expression levels of angiotensinogen (AGT), hypoxia inducible factor (HIF)1α and melanoma cell adhesion molecule (MCAM; CD146) in 101 human samples (69 biopsy, 12 resection) from affected ileum (inflamed CD cases, n=36) and unaffected ileum (non-inflamed CD cases, n=45 and controls, n=20). Immunohistochemistry for angiotensinogen was also performed. The study was of case-control design in a tertiary care setting.
  
  
  RESULTS
  Ileal expression of AGT was lower in CD cases compared to controls (p<0.0001), in inflamed CD samples (p=0.017) and current smokers (p=0.02). HIF1α expression was lower in non-inflamed CD biopsy samples than controls (p=0.006). The presence of disease-associated NOD2 variants was associated with increased expression of markers of angiogenesis (HIF1α p=0.009; MCAM p=0.007) in inflamed CD samples. Angiotensinogen immunohistochemical staining supported the quantitative RT-PCR expression findings.
  
  
  CONCLUSIONS
  Angiotensinogen expression is down regulated in human ileal CD, particularly in the presence of inflammation and current cigarette smoking, implicating the mesenteric vasculature and mucosal hypoxia as co-factors in ileal CD pathogenesis. A novel reduction in HIF1α expression in non-inflamed ileal mucosa in CD patients was also demonstrated.
authors.affiliation: QIMR Berghofer Medical Research Institute and University of Queensland School of Medicine, Herston Campus;Department of Gastroenterology, Royal Brisbane and Women's Hospital, Brisbane, Australia. georgia@drgeorgiahume.com.au.
authors.forename: Georgia E
authors.initials: GE
authors.lastname: Hume
authors.affiliation: Health National Research Flagship, CSIRO Mathematics, Information and Statistics, RBWH Herston, Australia.
authors.forename: James D
authors.initials: JD
authors.lastname: Doecke
authors.affiliation: QIMR Berghofer Medical Research Institute and University of Queensland School of Medicine, Herston Campus, Brisbane, Australia.
authors.forename: Ning
authors.initials: N
authors.lastname: Huang
authors.affiliation: QIMR Berghofer Medical Research Institute and University of Queensland School of Medicine, Herston Campus, Brisbane, Australia.
authors.forename: Elizabeth V
authors.initials: EV
authors.lastname: Fowler
authors.affiliation: Envoi Pathology, Herston, Brisbane, Queensland, Australia.
authors.forename: Ian S
authors.initials: IS
authors.lastname: Brown
authors.affiliation: QIMR Berghofer Medical Research Institute and University of Queensland School of Medicine, Herston Campus, Brisbane, Australia.
authors.forename: Lisa A
authors.initials: LA
authors.lastname: Simms
authors.affiliation: QIMR Berghofer Medical Research Institute and University of Queensland School of Medicine, Herston Campus;Department of Gastroenterology, Royal Brisbane and Women's Hospital, Brisbane, Australia.
authors.forename: Graham L
authors.initials: GL
authors.lastname: Radford-Smith
mesh_terms: D000328:Adult; D000368:Aged; D042501:Angiogenic Proteins / Q000032:analysis* / Q000235:genetics; D000808:Angiotensinogen / Q000032:analysis* / Q000235:genetics; D051929:CD146 Antigen / Q000235:genetics; D016022:Case-Control Studies; D003424:Crohn Disease / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D005260:Female; D005786:Gene Expression Regulation; D005838:Genotype; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000032:analysis* / Q000235:genetics; D007082:Ileum / Q000737:chemistry* / Q000473:pathology; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D009389:Neovascularization, Pathologic / Q000235:genetics; D053473:Nod2 Signaling Adaptor Protein / Q000235:genetics; D010641:Phenotype; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D012907:Smoking / Q000009:adverse effects; D055815:Young Adult
chemical_list: C534931:AGT protein, human; D042501:Angiogenic Proteins; D051929:CD146 Antigen; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C497902:MCAM protein, human; C429018:NOD2 protein, human; D053473:Nod2 Signaling Adaptor Protein; D012333:RNA, Messenger; D000808:Angiotensinogen