Hume Georgia E, Doecke James D, Huang Ning, Fowler Elizabeth V, Brown Ian S, Simms Lisa A, Radford-Smith Graham L
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.
Health National Research Flagship, CSIRO Mathematics, Information and Statistics, RBWH Herston, Australia.
J Gastrointestin Liver Dis. 2016 Mar;25(1):39-48. doi: 10.15403/jgld.2014.1121.251.chr.
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.
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.
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.
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.
血管紧张素II（AII）是一种强大的内脏血管收缩剂，具有促炎和促纤维化特性。血管紧张素转换酶（ACE）抑制剂和AII受体拮抗剂在结肠炎动物模型中具有治疗作用。本病例对照研究的目的是确定血管紧张素原及相关基因在人类回肠克罗恩病中的表达。
我们使用定量实时聚合酶链反应（RT-PCR），检测了101份人类样本（69份活检样本，12份切除样本）中血管紧张素原（AGT）、缺氧诱导因子（HIF）1α和黑色素瘤细胞黏附分子（MCAM；CD146）的mRNA表达水平，这些样本来自受累回肠（炎症性克罗恩病病例，n = 36）和未受累回肠（非炎症性克罗恩病病例，n = 45和对照组，n = 20）。还进行了血管紧张素原的免疫组织化学检测。该研究是在三级医疗环境中进行的病例对照设计。
与对照组相比，克罗恩病病例的回肠AGT表达较低（p < 0.0001），在炎症性克罗恩病样本中（p = 0.017）以及当前吸烟者中（p = 0.02）也是如此。非炎症性克罗恩病活检样本中的HIF1α表达低于对照组（p = 0.006）。疾病相关NOD2变体的存在与炎症性克罗恩病样本中血管生成标志物的表达增加相关（HIF1α p = 0.009；MCAM p = 0.007）。血管紧张素原免疫组织化学染色支持定量RT-PCR表达结果。
血管紧张素原表达在人类回肠克罗恩病中下调，特别是在存在炎症和当前吸烟的情况下，这表明肠系膜血管系统和黏膜缺氧是回肠克罗恩病发病机制中的共同因素。还证明了克罗恩病患者非炎症性回肠黏膜中HIF1α表达的新降低。
