title: NKX2-3 transcriptional regulation of endothelin-1 and VEGF signaling in human intestinal microvascular endothelial cells.
abstract: BACKGROUND
  NKX2-3 is associated with inflammatory bowel disease (IBD). NKX2-3 is expressed in microvascular endothelial cells and the muscularis mucosa of the gastrointestinal tract. Human intestinal microvascular endothelial cells (HIMECs) are actively involved in the pathogenesis of IBD and IBD-associated microvascular dysfunction. To understand the cellular function of NKX2-3 and its potential role underlying IBD pathogenesis, we investigated the genes regulated by NKX2-3 in HIMEC using cDNA microarray.
  
  
  RESULTS
  NKX2-3 expression was suppressed by shRNA in two HIMEC lines and gene expression was profiled by cDNA microarray. Pathway Analysis was used to identify gene networks according to biological functions and associated pathways. Validation of microarray and genes expression in intestinal tissues was assessed by RT-PCR. NKX2-3 regulated genes are involved in immune and inflammatory response, cell proliferation and growth, metabolic process, and angiogenesis. Several inflammation and angiogenesis related signaling pathways that play important roles in IBD were regulated by NKX2-3, including endothelin-1 and VEGF-PI3K/AKT-eNOS. Expression levels of NKX2-3, VEGFA, PI3K, AKT, and eNOS are increased in intestinal tissues from IBD patients and expression levels of EDN1 are decreased in intestinal tissues from IBD patients. These results demonstrated the important roles of NKX2-3, VEGF, PI3K, AKT, eNOS, and EDN1 in IBD pathogenesis. Correlation analysis showed a positive correlation between mRNA expression of NKX2-3 and VEGFA and a negative correlation between mRNA expression of NKX2-3 and EDN1 in intestinal tissues from IBD patients.
  
  
  CONCLUSIONS
  NKX2-3 may play an important role in IBD pathogenesis by regulating endothelin-1 and VEGF signaling in HIMECs.
authors.affiliation: Department of Surgery, Pennsylvania State University, Hershey, Pennsylvania, United States of America.
authors.forename: Wei
authors.initials: W
authors.lastname: Yu
authors.forename: John P
authors.initials: JP
authors.lastname: Hegarty
authors.forename: Arthur
authors.initials: A
authors.lastname: Berg
authors.forename: Xi
authors.initials: X
authors.lastname: Chen
authors.forename: Gail
authors.initials: G
authors.lastname: West
authors.forename: Ashley A
authors.initials: AA
authors.lastname: Kelly
authors.forename: Yunhua
authors.initials: Y
authors.lastname: Wang
authors.forename: Lisa S
authors.initials: LS
authors.lastname: Poritz
authors.forename: Walter A
authors.initials: WA
authors.lastname: Koltun
authors.forename: Zhenwu
authors.initials: Z
authors.lastname: Lin
mesh_terms: D000328:Adult; D002460:Cell Line; D003710:Demography; D042783:Endothelial Cells / Q000201:enzymology / Q000378:metabolism*; D019332:Endothelin-1 / Q000235:genetics* / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation; D055785:Gene Knockdown Techniques; D053263:Gene Regulatory Networks / Q000235:genetics; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D015212:Inflammatory Bowel Diseases / Q000235:genetics / Q000473:pathology; D007422:Intestines / Q000473:pathology; D008297:Male; D055806:Microvessels / Q000473:pathology*; D008875:Middle Aged; D052250:Nitric Oxide Synthase Type III / Q000235:genetics / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D015203:Reproducibility of Results; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics* / Q000378:metabolism
chemical_list: D019332:Endothelin-1; D018398:Homeodomain Proteins; D052250:Nitric Oxide Synthase Type III; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D014157:Transcription Factors; D042461:Vascular Endothelial Growth Factor A; C534957:NKX2-3 protein, human; C467484:VEGFA protein, human; C496314:NOS3 protein, human