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Arteriosclerosis, Thrombosis, and Vascular Biology. 2000;20:385-391

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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2000;20:385.)
© 2000 American Heart Association, Inc.


Vascular Biology

Convergence of Redox-Sensitive and Mitogen-Activated Protein Kinase Signaling Pathways in Tumor Necrosis Factor-{alpha}–Mediated Monocyte Chemoattractant Protein-1 Induction in Vascular Smooth Muscle Cells

Gilles W. De Keulenaer; Masuko Ushio-Fukai; QiQin Yin; Andrew B. Chung; P. Reid Lyons; Nobukazu Ishizaka; Kalpana Rengarajan; W. Robert Taylor; R. Wayne Alexander; Kathy K. Griendling

From the Division of Cardiology, Emory University School of Medicine, Atlanta, Ga.

Correspondence to Kathy K. Griendling, PhD, Emory University, Division of Cardiology, 1639 Pierce Dr, 319 WMB, Atlanta, GA 30322. E-mail kgriend{at}emory.edu

Abstract—Monocyte chemoattractant protein-1 (MCP-1) is an important component of the inflammatory response of the vessel wall and has been shown to be regulated by cytokines, such as tumor necrosis factor-{alpha} (TNF-{alpha}). However, the precise signaling pathways leading to MCP-1 induction have not been fully elucidated in vascular smooth muscle cells (VSMCs). Cytokine signal transduction involves protein kinases as well as reactive oxygen species (ROS). The relation between these 2 factors is not clear. In this study, we show that TNF-{alpha} induces a parallel phosphorylation of extracellular signal–regulated kinase 1/2 (ERK1/2) and p38 mitogen-activated protein kinase (p38MAPK) and increases MCP-1 mRNA expression in cultured VSMCs. Inhibition of ERK1/2 but not p38MAPK caused a partial attenuation of MCP-1 induction (43±10% inhibition). Incubation of VSMCs with multiple antioxidants (diphenylene iodonium, liposomal superoxide dismutase, catalase, N-acetylcysteine, dimethylthiourea, and pyrrolidine dithiocarbamate) had no effect on TNF-{alpha}–mediated MCP-1 upregulation. However, simultaneous blockade of the ERK1/2 and ROS pathways by using PD098059 combined with diphenylene iodonium or N-acetylcysteine potently enhanced the ability of MAPK kinase inhibitors to abrogate MCP-1 mRNA expression (100±2% inhibition). Thus, parallel ROS-dependent and ERK1/2-dependent pathways converge to regulate TNF-{alpha}–induced MCP-1 gene expression in VSMCs. These data unmask a complex but organized integration of ROS and protein kinases that mediates cytokine-induced vascular inflammatory gene expression.


Key Words: monocyte chemoattractant protein-1 • smooth muscle cells • reactive oxygen species • cytokines • tyrosine kinase




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