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(Circulation Research. 2003;93:311.)
© 2003 American Heart Association, Inc.

Molecular Medicine

Homocysteine Mediated Expression and Secretion of Monocyte Chemoattractant Protein-1 and Interleukin-8 in Human Monocytes

Xiaokun Zeng, Jing Dai, Daniel G. Remick, Xian Wang

From the Institute of Vascular Medicine (X.Z., J.D., X.W.), Peking University Third Hospital; Department of Physiology (X.W.) and Reference Laboratory of Education Ministry on Molecular Cardiology (X.W.), Peking University Basic Medical College, Beijing, People’s Republic of China; and Department of Pathology (D.G.R.), University of Michigan Medical School, Ann Arbor, Mich.

Correspondence to Dr Xian Wang, Department of Physiology, Basic Medical College, Peking University, Beijing 100083, People’s Republic of China. E-mail xwang{at}bjmu.edu.cn

Homocysteine (Hcy) is an independent risk factor for cardiovascular disease. Monocyte chemoattractant protein-1 (MCP-1) and interleukin-8 (IL-8) are major chemokines for leukocyte trafficking and have been identified in atheromatous plaques. MCP-1 and IL-8 have been found to express mainly by macrophages in human lesion. We undertook this study to determine whether Hcy could induce the secretion of chemokines from human monocytes and, if so, to explore the mediating mechanism. We found that clinically relevant levels of Hcy (10 to 1000 µmol/L) increased the protein secretion and mRNA expression as well as activity of MCP-1 and IL-8 in cultured primary human monocytes. These effects of Hcy were primarily mediated by reactive oxygen species (ROS) through NAD(P)H oxidase, because Hcy could upregulate the production of ROS and the inhibitors of protein kinase C, calmodulin, free radical scavengers, or NAD(P)H oxidase abolished Hcy-induced ROS production and MCP-1 and IL-8 secretion in these cells. Furthermore, the inhibitors of mitogen-activated protein kinase (p38 and extracellular signal-regulated kinase 1/2) and nuclear factor-B or the activator of peroxisome proliferator-activated receptor (PPAR) significantly decreased Hcy-induced MCP-1 and IL-8 secretion in these cells. These data indicate that pathophysiological levels of Hcy can alter human monocyte function by upregulating MCP-1 and IL-8 expression and secretion via enhanced formation of intracellular ROS originated from NAD(P)H oxidase source via calmodulin or protein kinase C signaling pathways and that Hcy-induced ROS subsequently activates mitogen-activated protein kinase (p38 and ERK1/2) and nuclear factor-B in a PPAR activator–sensitive manner. Thus, activation of PPAR may become a therapeutic target for preventing Hcy-induced proatherogenic effects.

Key Words: homocysteine • monocytes • atherosclerosis • monocyte chemoattractant protein-1 • interleukin-8

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