Macrophage inflammatory protein-1β induced cell adhesion with increased intracellular reactive oxygen species

To investigate the role of macrophage inflammatory protein-1 beta (MIP-1 beta) in the development of atherosclerosis, we designed an in vitro study to elucidate the mechanisms of monocyte-endothelium adhesion via intracellular reactive oxygen species (ROS). Angiotensin II (Ang II) was used as a positive control. Furthermore, we examined the efficacy of MIP-1 beta as a predictor of stroke and cardiovascular events in hypertensive patients. MIP-1 beta or AngII stimulation significantly increased ROS production and adhesion of THP-1 cells to inflamed human umbilical vein endothelial cells. Cell adhesion and ROS production were inhibited in stimulated THP-1 cells by: inhibition of ROS signaling with N-acetylcysteine, diphenyleneiodonium, or PEG-Catalase; inhibition of PI3K gamma with siRNA or LY294002; and by Rac1 siRNA. The MIP-1 beta or AngII stimulation did not increase surface expression of integrins, very late antigen 4 (VLA-4) and lymphocyte function-associated antigen 1 (LFA-1), but cell adhesion was reduced by using an antiVLA-4 or an antiLFA-1 antibody. Moreover, cell adhesion and ROS production stimulated with MIP-1 beta or AngII were completely inhibited by fluvastatin. In our clinical study, patients with the highest quartile of MIP-1 beta showed a higher risk of stroke and cardiovascular events by a Cox proportional-hazards model. In conclusion, MIP-1 beta directly induced cell adhesion to endothelial cells through oxidative stress via PI3k-Rac1 cascades. Serum MIP-1 beta level might be a useful predictor for cerebro-cardiovascular events in hypertensive patients. Condensed abstract: We designed an in vitro investigation to examine the role of MIP-1 beta on the development of atherosclerosis, including cell adhesion involving CAMS and ROS production, compared with angiotensin II. Furthermore, we investigated the prognostic impact of MIP-1 beta on stroke and cardiovascular events in hypertensive patients in a small cohort study. (C) 2009 Elsevier Inc. All rights reserved.