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(Circulation. 2003;108:1113.)
© 2003 American Heart Association, Inc.

Basic Science Reports

A20 Protects From CD40-CD40 Ligand-Mediated Endothelial Cell Activation and Apoptosis

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

From the Immunobiology Research Center, Department of Surgery and Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Mass.

Correspondence to Christiane Ferran, MD, PhD, Immunobiology Research Center, 99 Brookline Ave, Boston MA 02215. E-mail cferran{at}caregroup.harvard.edu

Received June 26, 2002; de novo received December 31, 2002; revision received April 22, 2003; accepted May 20, 2003.

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-B and upregulates IB, E-selectin, and tissue factor (TF) reporter activity. Coexpression of A20 inhibits NF-B and upregulation of IB and E-Selectin but not TF, suggesting that CD40 induces TF in a non–NF-B–dependent manner. In human coronary artery ECs (HCAECs), adenovirus-mediated overexpression of A20 blocks physiological, CD40-induced activation of NF-B, upstream of IB 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-B and induces apoptosis in ECs, both of which are inhibited by A20 overexpression.

Conclusion— 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.

Key Words: endothelium • atherosclerosis • gene therapy • thrombosis • inflammation

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