Divergent and convergent effects on gene expression and function in acute versus chronic endothelial activation

Gangaraju Rajashekhar, Matthew Grow, Antje Willuweit, Carolyn E. Patterson, Matthias Clauss

Research output: Contribution to journalArticle

24 Citations (Scopus)

Abstract

Activation of the vascular endothelium with cytokines such as TNF is widely used to study the role of the vasculature in proinflammatory disease. To gain insight into mechanisms of prolonged vascular endothelial activation we compared changes in gene expression induced by continuous activation in stable tmTNF-expressing cells with changes due to acute TNF challenge in vitro. Affymetrix Genechip analysis was performed on RNA from control, acute and continuous TNF-activated endothelial cells. Only 36% of the significant changes in gene expression were convergent between the acute and continuously activated endothelial cells compared with the control. From the divergently regulated genes, for example the cytokine ENA-78 was specifically induced in chronically activated cells, while E-selectin, a cell adhesion molecule, was upregulated only in acutely activated endothelial cells. Antioxidant SOD gene induction was noted in acute activation, while a regulatory NADPH oxidase subunit was selectively upregulated in continuously activated endothelium in accordance with significant reactive oxygen species induction occurred only in these cells. Accordingly, p38 and ERK1/2, two MAP kinases downstream of reactive oxygen species, were activated in stable transmembrane-spanning precursor (tm) TNF-expressing cells and were refractory to activation with soluble TNF or VEGF. In consequence, the increased p38 MAP kinase activity contributed to increased endothelial cell migration in tmTNF-expressing cells. These data suggest that continuous activation of endothelial cells leads to specific expression and functional changes, consistent with alterations observed in dysfunctional endothelium exposed to or involved in chronic inflammation.

Original languageEnglish
Pages (from-to)104-113
Number of pages10
JournalPhysiological Genomics
Volume31
Issue number1
DOIs
StatePublished - Sep 19 2007

Fingerprint

Endothelial Cells
Gene Expression
Endothelium
Reactive Oxygen Species
Cytokines
E-Selectin
NADPH Oxidase
Mitogen-Activated Protein Kinase 1
Vascular Endothelium
Cell Adhesion Molecules
p38 Mitogen-Activated Protein Kinases
Vascular Endothelial Growth Factor A
Genes
Cell Movement
Blood Vessels
Antioxidants
RNA
Inflammation

Keywords

  • Genechip
  • Microarray
  • Migration
  • p38 mitogen-activated protein kinase
  • Tumor necrosis factor

ASJC Scopus subject areas

  • Physiology
  • Genetics

Cite this

Divergent and convergent effects on gene expression and function in acute versus chronic endothelial activation. / Rajashekhar, Gangaraju; Grow, Matthew; Willuweit, Antje; Patterson, Carolyn E.; Clauss, Matthias.

In: Physiological Genomics, Vol. 31, No. 1, 19.09.2007, p. 104-113.

Research output: Contribution to journalArticle

Rajashekhar, Gangaraju ; Grow, Matthew ; Willuweit, Antje ; Patterson, Carolyn E. ; Clauss, Matthias. / Divergent and convergent effects on gene expression and function in acute versus chronic endothelial activation. In: Physiological Genomics. 2007 ; Vol. 31, No. 1. pp. 104-113.
@article{ebf72b70ce2e4d09957dafec9cac85af,
title = "Divergent and convergent effects on gene expression and function in acute versus chronic endothelial activation",
abstract = "Activation of the vascular endothelium with cytokines such as TNF is widely used to study the role of the vasculature in proinflammatory disease. To gain insight into mechanisms of prolonged vascular endothelial activation we compared changes in gene expression induced by continuous activation in stable tmTNF-expressing cells with changes due to acute TNF challenge in vitro. Affymetrix Genechip analysis was performed on RNA from control, acute and continuous TNF-activated endothelial cells. Only 36{\%} of the significant changes in gene expression were convergent between the acute and continuously activated endothelial cells compared with the control. From the divergently regulated genes, for example the cytokine ENA-78 was specifically induced in chronically activated cells, while E-selectin, a cell adhesion molecule, was upregulated only in acutely activated endothelial cells. Antioxidant SOD gene induction was noted in acute activation, while a regulatory NADPH oxidase subunit was selectively upregulated in continuously activated endothelium in accordance with significant reactive oxygen species induction occurred only in these cells. Accordingly, p38 and ERK1/2, two MAP kinases downstream of reactive oxygen species, were activated in stable transmembrane-spanning precursor (tm) TNF-expressing cells and were refractory to activation with soluble TNF or VEGF. In consequence, the increased p38 MAP kinase activity contributed to increased endothelial cell migration in tmTNF-expressing cells. These data suggest that continuous activation of endothelial cells leads to specific expression and functional changes, consistent with alterations observed in dysfunctional endothelium exposed to or involved in chronic inflammation.",
keywords = "Genechip, Microarray, Migration, p38 mitogen-activated protein kinase, Tumor necrosis factor",
author = "Gangaraju Rajashekhar and Matthew Grow and Antje Willuweit and Patterson, {Carolyn E.} and Matthias Clauss",
year = "2007",
month = "9",
day = "19",
doi = "10.1152/physiolgenomics.00157.2006",
language = "English",
volume = "31",
pages = "104--113",
journal = "Physiological Genomics",
issn = "1094-8341",
publisher = "American Physiological Society",
number = "1",

}

TY - JOUR

T1 - Divergent and convergent effects on gene expression and function in acute versus chronic endothelial activation

AU - Rajashekhar, Gangaraju

AU - Grow, Matthew

AU - Willuweit, Antje

AU - Patterson, Carolyn E.

AU - Clauss, Matthias

PY - 2007/9/19

Y1 - 2007/9/19

N2 - Activation of the vascular endothelium with cytokines such as TNF is widely used to study the role of the vasculature in proinflammatory disease. To gain insight into mechanisms of prolonged vascular endothelial activation we compared changes in gene expression induced by continuous activation in stable tmTNF-expressing cells with changes due to acute TNF challenge in vitro. Affymetrix Genechip analysis was performed on RNA from control, acute and continuous TNF-activated endothelial cells. Only 36% of the significant changes in gene expression were convergent between the acute and continuously activated endothelial cells compared with the control. From the divergently regulated genes, for example the cytokine ENA-78 was specifically induced in chronically activated cells, while E-selectin, a cell adhesion molecule, was upregulated only in acutely activated endothelial cells. Antioxidant SOD gene induction was noted in acute activation, while a regulatory NADPH oxidase subunit was selectively upregulated in continuously activated endothelium in accordance with significant reactive oxygen species induction occurred only in these cells. Accordingly, p38 and ERK1/2, two MAP kinases downstream of reactive oxygen species, were activated in stable transmembrane-spanning precursor (tm) TNF-expressing cells and were refractory to activation with soluble TNF or VEGF. In consequence, the increased p38 MAP kinase activity contributed to increased endothelial cell migration in tmTNF-expressing cells. These data suggest that continuous activation of endothelial cells leads to specific expression and functional changes, consistent with alterations observed in dysfunctional endothelium exposed to or involved in chronic inflammation.

AB - Activation of the vascular endothelium with cytokines such as TNF is widely used to study the role of the vasculature in proinflammatory disease. To gain insight into mechanisms of prolonged vascular endothelial activation we compared changes in gene expression induced by continuous activation in stable tmTNF-expressing cells with changes due to acute TNF challenge in vitro. Affymetrix Genechip analysis was performed on RNA from control, acute and continuous TNF-activated endothelial cells. Only 36% of the significant changes in gene expression were convergent between the acute and continuously activated endothelial cells compared with the control. From the divergently regulated genes, for example the cytokine ENA-78 was specifically induced in chronically activated cells, while E-selectin, a cell adhesion molecule, was upregulated only in acutely activated endothelial cells. Antioxidant SOD gene induction was noted in acute activation, while a regulatory NADPH oxidase subunit was selectively upregulated in continuously activated endothelium in accordance with significant reactive oxygen species induction occurred only in these cells. Accordingly, p38 and ERK1/2, two MAP kinases downstream of reactive oxygen species, were activated in stable transmembrane-spanning precursor (tm) TNF-expressing cells and were refractory to activation with soluble TNF or VEGF. In consequence, the increased p38 MAP kinase activity contributed to increased endothelial cell migration in tmTNF-expressing cells. These data suggest that continuous activation of endothelial cells leads to specific expression and functional changes, consistent with alterations observed in dysfunctional endothelium exposed to or involved in chronic inflammation.

KW - Genechip

KW - Microarray

KW - Migration

KW - p38 mitogen-activated protein kinase

KW - Tumor necrosis factor

UR - http://www.scopus.com/inward/record.url?scp=34548851951&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=34548851951&partnerID=8YFLogxK

U2 - 10.1152/physiolgenomics.00157.2006

DO - 10.1152/physiolgenomics.00157.2006

M3 - Article

C2 - 17566077

AN - SCOPUS:34548851951

VL - 31

SP - 104

EP - 113

JO - Physiological Genomics

JF - Physiological Genomics

SN - 1094-8341

IS - 1

ER -