title: Macrophage inflammatory protein-1beta induced cell adhesion with increased intracellular reactive oxygen species.
abstract: To investigate the role of macrophage inflammatory protein-1 beta (MIP-1beta) 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 (AngII) was used as a positive control. Furthermore, we examined the efficacy of MIP-1beta as a predictor of stroke and cardiovascular events in hypertensive patients. MIP-1beta 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 PI3Kgamma 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-1beta or AngII were completely inhibited by fluvastatin. In our clinical study, patients with the highest quartile of MIP-1beta showed a higher risk of stroke and cardiovascular events by a Cox proportional-hazards model. In conclusion, MIP-1beta directly induced cell adhesion to endothelial cells through oxidative stress via PI3k-Rac1 cascades. Serum MIP-1beta level might be a useful predictor for cerebro-cardiovascular events in hypertensive patients.
  
  
  CONCLUSIONS
  We designed an in vitro investigation to examine the role of MIP-1beta 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-1beta on stroke and cardiovascular events in hypertensive patients in a small cohort study.
authors.affiliation: Department of Geriatric Medicine, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita 565-0871, Japan.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Tatara
authors.forename: Mitsuru
authors.initials: M
authors.lastname: Ohishi
authors.forename: Koichi
authors.initials: K
authors.lastname: Yamamoto
authors.forename: Atsushi
authors.initials: A
authors.lastname: Shiota
authors.forename: Norihiro
authors.initials: N
authors.lastname: Hayashi
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Iwamoto
authors.forename: Masao
authors.initials: M
authors.lastname: Takeda
authors.forename: Takashi
authors.initials: T
authors.lastname: Takagi
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Katsuya
authors.forename: Toshio
authors.initials: T
authors.lastname: Ogihara
authors.forename: Hiromi
authors.initials: H
authors.lastname: Rakugi