title: Losartan inhibits monocytic adhesion induced by ADMA via downregulation of chemokine receptors in monocytes.
abstract: OBJECTIVE
  Asymmetric dimethylarginine (ADMA), an endogenous nitric oxide synthase (NOS) inhibitor, can induce the adhesiveness of monocytes to vascular endothelium, and chemokines play an important role in this process. The present study was carried out to test whether the inhibitory effect of losartan on ADMA-induced monocytic adhesion is mediated by chemokine receptors.
  
  
  METHODS
  Human monocytoid cells (THP-1) were incubated with exogenous ADMA (30 microM) for 4 or 24 h in the absence or presence of losartan. The monocytic adhesion, the levels of chemokines, and the expression of chemokine receptors were determined. The possible signal pathway was also explored.
  
  
  RESULTS
  In cultured monocytes, ADMA (30 microM) markedly increased monocytic adhesion to endothelial cells, elevated the levels of monocyte chemoattractant protein-1 (MCP-1) and interleukin-8 (IL-8), and upregulated the mRNA expression of chemokine receptors CCR2 and CXCR2. Exposure to ADMA (30 microM) significantly induced the generation of intracellular reactive oxygen species (ROS) and activation of nuclear factor (NF)-kappaB. Pretreatment with AT1 receptor blocker (ARB) losartan (1, 3, 10 microM) attenuated monocytic adhesiveness elicited by ADMA and downregulated the expression of CCR2 and CXCR2 mRNA, accompanied by a significant decrease in ROS generation and NF-kappaB activity and expression.
  
  
  CONCLUSIONS
  The present study suggests that the inhibitory effect of losartan on ADMA-induced monocytic adhesion may be related to downregulation of chemokine receptors by inhibiting the ROS/NF-kappaB pathway.
authors.affiliation: Department of Geriatric Medicine, Xiang-Ya Hospital, Central South University, Xiang-Ya Road #141, Changsha, Hunan 410008, People's Republic of China.
authors.forename: Mei-Fang
authors.initials: MF
authors.lastname: Chen
authors.forename: Yuan-Jian
authors.initials: YJ
authors.lastname: Li
authors.forename: Tian-Lun
authors.initials: TL
authors.lastname: Yang
authors.forename: Bin
authors.initials: B
authors.lastname: Lou
authors.forename: Xiu-Mei
authors.initials: XM
authors.lastname: Xie
mesh_terms: D001120:Arginine / Q000031:analogs & derivatives / Q000494:pharmacology; D002448:Cell Adhesion / Q000187:drug effects; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000096:biosynthesis; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects*; D042783:Endothelial Cells / Q000187:drug effects; D006801:Humans; D016209:Interleukin-8 / Q000096:biosynthesis; D019808:Losartan / Q000494:pharmacology*; D009000:Monocytes / Q000166:cytology* / Q000187:drug effects* / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis; D019707:Receptors, Chemokine / Q000235:genetics / Q000378:metabolism*; D013997:Time Factors
chemical_list: D018932:Chemokine CCL2; D016209:Interleukin-8; D016328:NF-kappa B; D012333:RNA, Messenger; D019707:Receptors, Chemokine; C018524:N,N-dimethylarginine; D001120:Arginine; D019808:Losartan