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(Circulation Research. 2002;91:798.)
© 2002 American Heart Association, Inc.

Molecular Medicine

Rac-Dependent Monocyte Chemoattractant Protein-1 Production Is Induced by Nutrient Deprivation

Neuza H.M. Lopes, Sanjay S. Vasudevan, David Gregg, Balakrishnan Selvakumar, Patrick J. Pagano, Herve Kovacic, Pascal J. Goldschmidt-Clermont

From the Division of Cardiology, Department of Medicine (N.H.M.L., S.S.V., D.G., B.S., P.J.G.-C.), Duke University Medical Center, Durham, NC; Henry Ford Hospital (P.J.P.), Detroit, Michigan; and Université de la Méditerranée (H.K.), Marseille, France.

Correspondence to Pascal J. Goldschmidt-Clermont, Division of Cardiology, Dept of Medicine, Duke University Medical Center, Box 3845, Durham NC-27710. E-mail golds017{at}mc.duke.edu

Under ischemic conditions, the vessel wall recruits inflammatory cells. Human aortic endothelial cells (HAECs) exposed to hypoxia followed by reoxygenation produce monocyte chemoattractant protein-1 (MCP-1); however, most experiments have been performed in the presence of nutrient deprivation (ND). We hypothesized that ND rather than hypoxia mediates endothelial MCP-1 production during ischemia, and that the small GTP-binding protein Rac1 and reactive oxygen species (ROS) are involved in this process. ND was generated by shifting HAECs from 10% to 1% FBS. Superoxide production by HAECs was increased 6 to 24 hours after ND, peaking at 18 hours. MCP-1 production was increased over a similar time frame, but peaked later at 24 hours. These effects were blocked by treatment with antioxidants such as superoxide dismutase mimetic and N-acetylcysteine (NAC), or NADPH oxidase inhibitors, DPI and gp91ds-tat. Superoxide and MCP-1 production were enhanced by RacV12 (constitutively active) in the absence of ND, and were inhibited by RacN17 (dominant-negative) adenoviral transduction under ND, suggesting that the small G-protein Rac1 is required. In conclusion, ND, an important component of ischemia, is sufficient to induce MCP-1 production by HAECs, and such production requires a functional Rac1, redox-dependent pathway.

Key Words: monocyte chemoattractant protein-1 • superoxide • Rac • nutrient deprivation • ischemia

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