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The regulated in development and DNA damage response 2 (REDD2) gene mediates human monocyte cell death through a

Jguirim-Souissi Imen1, Ludivine Billiet, Clarisse Cuaz-Pérolin

  • 1Université Pierre et Marie Curie, Paris, France.

Free Radical Biology & Medicine
|March 10, 2009
PubMed

Insights

The regulated in development and DNA damage response 2 (REDD2) gene promotes reactive oxygen species (ROS) production and oxidative stress in macrophages, potentially by reducing thioredoxin-1 (Trx-1) levels, contributing to atherosclerosis.

Area of Science:

  • Molecular Biology
  • Cardiovascular Research
  • Cellular Biology

Background:

  • The regulated in development and DNA damage response 2 (REDD2) gene is upregulated in human atherosclerotic lesions and oxidized low-density lipoprotein (LDL)-induced macrophage death.
  • The precise mechanism by which REDD2 influences macrophage response to oxidized LDL remains unclear.

Purpose of the Study:

  • To elucidate the molecular mechanism underlying REDD2's role in oxidized LDL-induced macrophage death sensitivity.
  • To investigate the relationship between REDD2, reactive oxygen species (ROS) production, and thioredoxin-1 (Trx-1) expression in macrophages.

Main Methods:

  • Transient transfection of U-937 monocytic cells with REDD2 expression vectors and small interfering RNA (siRNA) against REDD2.
  • Measurement of REDD2 and thioredoxin-1 (Trx-1) mRNA and protein levels.
  • Assessment of reactive oxygen species (ROS) production and oxidative modification of LDL.
  • Analysis of proapoptotic (Bax) and antiapoptotic (Bcl2) gene expression.

Main Results:

  • REDD2 overexpression significantly increased ROS production and LDL oxidation.
  • REDD2 overexpression led to a marked decrease in both Trx-1 mRNA and protein levels.
  • Silencing REDD2 with siRNA resulted in decreased REDD2 and increased Trx-1 levels.
  • REDD2 overexpression modulated Bax and Bcl2 expression, favoring apoptosis.
  • Macrophages from atherosclerotic lesions showed inverse expression patterns of REDD2 and Trx-1.

Conclusions:

  • REDD2 promotes ROS production and oxidative stress in macrophages, likely through the downregulation of Trx-1.
  • These findings suggest a novel mechanism for REDD2's contribution to the pathogenesis of atherosclerosis.
  • The inverse relationship between REDD2 and Trx-1 in patient lesions highlights their potential interplay in disease progression.

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