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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2004;24:1830.)
© 2004 American Heart Association, Inc.

Vascular Biology

REDD2 Gene Is Upregulated by Modified LDL or Hypoxia and Mediates Human Macrophage Cell Death

C. Cuaz-Pérolin; C. Furman; G. Larigauderie; L. Legedz; C. Lasselin; C. Copin; M. Jaye; G. Searfoss; K.T. Yu; N. Duverger; A. Nègre-Salvayre; J.-C. Fruchart; M. Rouis

From INSERM U-545 (C.C.-P., C.F., G.L., C.L., C.C., J.-C.F., M.R.) and Institut Pasteur de Lille, Lille, France; and INSERM U-331 (L.L.), Faculté de médecine René Laënnec, Lyon, France.

Correspondence to M. Rouis, 1 rue du Professeur Calmette, Institut Pasteur de Lille, 59019 Lille, France. E-mail mustapha.rouis{at}pasteur-lille.fr

Objective— Cholesterol accumulation in macrophages is known to alter macrophage biology. In this article we studied the impact of macrophage cholesterol loading on gene expression and identified a novel gene implicated in cell death.

Methods and Results— The regulated in development and DNA damage response 2 (REDD2) gene was strongly upregulated as THP-1 macrophages are converted to foam cells. These results were confirmed by Northern blot of RNA from human monocyte-derived macrophages (HMDM) treated with oxidized LDL (oxLDL). Human REDD2 shares 86% amino acid sequence identity with murine RTP801-like protein, which is 33% identical to RTP801, a hypoxia-inducible factor 1-responsive gene involved in apoptosis. Treatment of HMDM with desferrioxamine, a molecule that mimics the effect of hypoxia, increased expression of REDD2 in a concentration-dependent fashion. Transfection of U-937 and HMEC cells with a REDD2 expression vector increased the sensitivity of the cells for oxLDL-induced cytotoxicity, by inducing a shift from apoptosis toward necrosis. In contrast, suppression of mRNA expression using siRNA approach resulted in increased resistance to oxLDL treatment.

Conclusion— We showed that stimulation of REDD2 expression in macrophages increases oxLDL-induced cell death, suggesting that REDD2 gene might play an important role in arterial pathology.

The regulated in development and DNA damage response 2 (REDD2) gene is highly expressed in macrophages foam cells and in human atherosclerotic plaques. REDD2 overexpression in U-937 monocytic cells and HMEC endothelial cells increased the sensitivity for oxLDL-induced cytotoxicity. Therefore, REDD2 might play an important role in arterial pathology.

Key Words: REDD2 • macrophages • atherosclerosis • hypoxia • oxLDL • necrosis • apoptosis

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