NKX2-3 transcriptional regulation of endothelin-1 and VEGF signaling in human intestinal microvascular endothelial cells

Wei Yu, John P. Hegarty, Arthur Berg, Xi Chen, Gail West, Ashley A. Kelly, Yunhua Wang, Lisa S. Poritz, Walter A. Koltun, Zhenwu Lin

Research output: Contribution to journalArticle

15 Citations (Scopus)

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. Methodology/Principal Findings: 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. Conclusion/Relevance: NKX2-3 may play an important role in IBD pathogenesis by regulating endothelin-1 and VEGF signaling in HIMECs.

Original languageEnglish (US)
Article numbere20454
JournalPLoS One
Volume6
Issue number5
DOIs
StatePublished - May 31 2011
Externally publishedYes

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endothelins
inflammatory bowel disease
Endothelial cells
Endothelin-1
Inflammatory Bowel Diseases
Vascular Endothelial Growth Factor A
endothelial cells
Endothelial Cells
phosphatidylinositol 3-kinase
Microarrays
pathogenesis
Phosphatidylinositol 3-Kinases
Tissue
Genes
angiogenesis
Oligonucleotide Array Sequence Analysis
Gene expression
Complementary DNA
inflammation
Gene Expression

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

Cite this

NKX2-3 transcriptional regulation of endothelin-1 and VEGF signaling in human intestinal microvascular endothelial cells. / Yu, Wei; Hegarty, John P.; Berg, Arthur; Chen, Xi; West, Gail; Kelly, Ashley A.; Wang, Yunhua; Poritz, Lisa S.; Koltun, Walter A.; Lin, Zhenwu.

In: PLoS One, Vol. 6, No. 5, e20454, 31.05.2011.

Research output: Contribution to journalArticle

Yu, W, Hegarty, JP, Berg, A, Chen, X, West, G, Kelly, AA, Wang, Y, Poritz, LS, Koltun, WA & Lin, Z 2011, 'NKX2-3 transcriptional regulation of endothelin-1 and VEGF signaling in human intestinal microvascular endothelial cells', PLoS One, vol. 6, no. 5, e20454. https://doi.org/10.1371/journal.pone.0020454
Yu, Wei ; Hegarty, John P. ; Berg, Arthur ; Chen, Xi ; West, Gail ; Kelly, Ashley A. ; Wang, Yunhua ; Poritz, Lisa S. ; Koltun, Walter A. ; Lin, Zhenwu. / NKX2-3 transcriptional regulation of endothelin-1 and VEGF signaling in human intestinal microvascular endothelial cells. In: PLoS One. 2011 ; Vol. 6, No. 5.
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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. Methodology/Principal Findings: 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. Conclusion/Relevance: NKX2-3 may play an important role in IBD pathogenesis by regulating endothelin-1 and VEGF signaling in HIMECs.",
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AU - Yu, Wei

AU - Hegarty, John P.

AU - Berg, Arthur

AU - Chen, Xi

AU - West, Gail

AU - Kelly, Ashley A.

AU - Wang, Yunhua

AU - Poritz, Lisa S.

AU - Koltun, Walter A.

AU - Lin, Zhenwu

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N2 - 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. Methodology/Principal Findings: 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. Conclusion/Relevance: NKX2-3 may play an important role in IBD pathogenesis by regulating endothelin-1 and VEGF signaling in HIMECs.

AB - 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. Methodology/Principal Findings: 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. Conclusion/Relevance: NKX2-3 may play an important role in IBD pathogenesis by regulating endothelin-1 and VEGF signaling in HIMECs.

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