Published online before print October 3, 2002, doi: 10.1161/01.RES.0000040421.54108.81
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Submitted on July 11, 2002
Revised on September 24, 2002
Accepted on September 25, 2002
Rac-Dependent Monocyte Chemoattractant Protein-1 Production Is Induced by Nutrient Deprivation
Neuza H.M. Lopes ;
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 Universite de la Mediterranee (H.K.), Marseille, France.
* To whom correspondence should be addressed. 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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