A20 protects from CD40-CD40 ligand-mediated endothelial cell activation and apoptosis.

A20 protects from CD40-CD40 ligand-mediated endothelial cell activation and apoptosis. Research Abstract Details 

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A20 protects from CD40-CD40 ligand-mediated endothelial cell activation and apoptosis. Abstract Text:

Christopher R Longo,Maria B Arvelo,Virendra I Patel,Soizic Daniel,Jerome Mahiou,Shane T Grey,Christiane Ferran,

BACKGROUND: CD40/CD40 ligand (CD40L) signaling is a potent activator of endothelial cells (ECs) and promoter of atherosclerosis. In this study, we investigate whether A20 (a gene we have shown to be antiinflammatory and antiapoptotic in ECs) can protect from CD40/CD40L-mediated EC activation. METHODS AND RESULTS: Overexpression of CD40, in a transient transfection system, activates the transcription factor NF-kappaB and upregulates IkappaBalpha, E-selectin, and tissue factor (TF) reporter activity. Coexpression of A20 inhibits NF-kappaB and upregulation of IkappaBalpha and E-Selectin but not TF, suggesting that CD40 induces TF in a non-NF-kappaB-dependent manner. In human coronary artery ECs (HCAECs), adenovirus-mediated overexpression of A20 blocks physiological, CD40-induced activation of NF-kappaB, upstream of IkappaBalpha degradation (Western blot) and subsequently upregulation of ICAM-1, VCAM-1, and E-selectin (flow cytometry). Although A20 does not block TF transcription its expression in HCAECs inhibits TF induction (colorimetric assay and RT-PCR) by blunting CD40 upregulation. We demonstrate that CD40 signaling induces apoptosis in a proinflammatory microenvironment. A20 overexpression protects from CD40-mediated EC apoptosis (DNA content analysis and trypan blue exclusion). We also demonstrate that signaling through CD40L activates NF-kappaB and induces apoptosis in ECs, both of which are inhibited by A20 overexpression. CONCLUSIONS: A20 works at multiple levels to protect ECs from CD40/CD40L mediated activation and apoptosis. A20-based therapy could be beneficial for the treatment of vascular diseases such as atherosclerosis and transplant-associated vasculopathy.

A20 protects from CD40-CD40 ligand-mediated endothelial cell activation and apoptosis. Publishing Authors By Initials

CR Longo,MB Arvelo,VI Patel,S Daniel,J Mahiou,ST Grey,C Ferran,

For similar genetic processes: gene expression regulation: up-regulation research abstracts see: genetic processes: gene expression regulation: up-regulation research

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A20 protects from CD40-CD40 ligand-mediated endothelial cell activation and apoptosis. Journal Published:

PUBLICATION TYPE: Research Support, U.S. Gov't,

Journal: Circulation

VOLUME: 108

Page Numbers: 1113-8

Journal Abbreviation: Circulation

ISSN: 1524-4539

DAY: 28

MONTH: 07

YEAR: 2003

A20 protects from CD40-CD40 ligand-mediated endothelial cell activation and apoptosis. Information

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LANGUAGE: eng

NlmUniqueID: 147763

A20 protects from CD40-CD40 ligand-mediated endothelial cell activation and apoptosis. Keywords Mesh Terms:

KEYWORDS: Up-Regulation

MESH TERMS: pharmacology

Chemical & Substance for Abstract: A20 protects from CD40-CD40 ligand-mediated endothelial cell activation and apoptosis. Information

Substance Name: TNFAIP3 protein, human

Registry Number: EC 6.3.2.19

Grant and Affiliation Information for A20 protects from CD40-CD40 ligand-mediated endothelial cell activation and apoptosis.

AFFILIATION: Immunobiology Research Center, Department of Surgery and Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Mass 02215, USA.

Country: United States

AGENCY: United States NHLBI

GRANT: R01 HL57791

ACRONYM: HL

MEDLINETA: Circulation

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