title: HMG-CoA reductase inhibition reduces monocyte CC chemokine receptor 2 expression and monocyte chemoattractant protein-1-mediated monocyte recruitment in vivo.
abstract: BACKGROUND
  The migration of circulating monocytes to the arterial wall during atherogenesis is largely modulated by activation of the CC chemokine receptor 2 (CCR2), a dominant monocyte chemotaxis receptor. The present study investigated whether 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibition affects CCR2 gene expression and CCR2-dependent monocyte recruitment.
  
  
  RESULTS
  Competitive reverse transcription-polymerase chain reaction analysis and flow cytometry showed that simvastatin, an HMG-CoA reductase inhibitor, dose-dependently reduced monocyte CCR2 mRNA and protein expression. Treatment of 21 normocholesterolemic men with simvastatin (20 mg/d for 2 weeks) decreased CCR2 protein and mRNA expression in circulating monocytes. Promoter and electrophoretic mobility shift assays showed that simvastatin activated a peroxisome proliferator response element in THP-1 monocytes. Moreover, simvastatin-induced CCR2 downregulation was completely reversed by the synthetic peroxisome proliferator-activated receptor-gamma antagonist GW9662. Simvastatin-treated monocytes showed little chemotaxis movement in response to monocyte chemoattractant protein-1 (MCP-1), a specific CCR2 ligand. Treatment of C57/BL6 mice with simvastatin (0.2 microg/g body weight IP, daily for 1 week) inhibited transmigration of CD80+ monocytes to the MCP-1-injected intraperitoneal space. Moreover, few circulating inflammatory cells from simvastatin-treated Sprague-Dawley rats (0.2 microg/g body weight IP, daily for 2 weeks) were recruited to the aortic wall of hypercholesterolemic littermates.
  
  
  CONCLUSIONS
  The inhibition of CCR2/MCP-1-dependent monocyte recruitment by simvastatin may prevent excessive accumulation of monocytes in the arterial wall during atherogenesis.
authors.affiliation: Asan Medical Center, University of Ulsan, College of Medicine, Seoul, Korea. steadyhan@amc.seoul.kr
authors.forename: Ki Hoon
authors.initials: KH
authors.lastname: Han
authors.forename: Jewon
authors.initials: J
authors.lastname: Ryu
authors.forename: Kyung Hee
authors.initials: KH
authors.lastname: Hong
authors.forename: Jesang
authors.initials: J
authors.lastname: Ko
authors.forename: Youngmi Kim
authors.initials: YK
authors.lastname: Pak
authors.forename: Jae-Bum
authors.initials: JB
authors.lastname: Kim
authors.forename: Seong Wook
authors.initials: SW
authors.lastname: Park
authors.forename: Jae Joong
authors.initials: JJ
authors.lastname: Kim
mesh_terms: D000813:Anilides / Q000494:pharmacology; D000818:Animals; D001011:Aorta / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured / Q000187:drug effects / Q000378:metabolism; D018932:Chemokine CCL2 / Q000378:metabolism*; D002634:Chemotaxis, Leukocyte / Q000187:drug effects*; D003864:Depression, Chemical; D004036:Diet, Atherogenic; D015536:Down-Regulation / Q000187:drug effects*; D004353:Drug Evaluation, Preclinical; D005260:Female; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D006937:Hypercholesterolemia / Q000378:metabolism / Q000473:pathology; D008297:Male; D008798:Mevalonic Acid / Q000032:analysis; D051379:Mice; D008810:Mice, Inbred C57BL; D009000:Monocytes / Q000737:chemistry / Q000187:drug effects*; D047495:PPAR gamma / Q000037:antagonists & inhibitors / Q000502:physiology; D011106:Polyisoprenyl Phosphates / Q000032:analysis; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D017207:Rats, Sprague-Dawley; D054390:Receptors, CCR2; D019707:Receptors, Chemokine / Q000096:biosynthesis* / Q000235:genetics; D000077154:Rosiglitazone; D012717:Sesquiterpenes; D019821:Simvastatin / Q000494:pharmacology*; D045162:Thiazolidinediones / Q000494:pharmacology
chemical_list: C457499:2-chloro-5-nitrobenzanilide; D000813:Anilides; C111835:CCL2 protein, human; C515334:CCR2 protein, human; C515335:Ccr2 protein, mouse; C515336:Ccr2 protein, rat; D018932:Chemokine CCL2; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D047495:PPAR gamma; D011106:Polyisoprenyl Phosphates; D012333:RNA, Messenger; D054390:Receptors, CCR2; D019707:Receptors, Chemokine; D012717:Sesquiterpenes; D045162:Thiazolidinediones; D000077154:Rosiglitazone; C004808:farnesyl pyrophosphate; D019821:Simvastatin; C002963:geranylgeranyl pyrophosphate; D008798:Mevalonic Acid