PMID- 15781755
OWN - NLM
STAT- MEDLINE
DCOM- 20050919
LR  - 20181201
IS  - 1524-4539 (Electronic)
IS  - 0009-7322 (Linking)
VI  - 111
IP  - 11
DP  - 2005 Mar 22
TI  - HMG-CoA reductase inhibition reduces monocyte CC chemokine receptor 2 expression 
      and monocyte chemoattractant protein-1-mediated monocyte recruitment in vivo.
PG  - 1439-47
AB  - 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. METHODS AND 
      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.
FAU - Han, Ki Hoon
AU  - Han KH
AD  - Asan Medical Center, University of Ulsan, College of Medicine, Seoul, Korea. 
      steadyhan@amc.seoul.kr
FAU - Ryu, Jewon
AU  - Ryu J
FAU - Hong, Kyung Hee
AU  - Hong KH
FAU - Ko, Jesang
AU  - Ko J
FAU - Pak, Youngmi Kim
AU  - Pak YK
FAU - Kim, Jae-Bum
AU  - Kim JB
FAU - Park, Seong Wook
AU  - Park SW
FAU - Kim, Jae Joong
AU  - Kim JJ
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Circulation
JT  - Circulation
JID - 0147763
RN  - 0 (2-chloro-5-nitrobenzanilide)
RN  - 0 (Anilides)
RN  - 0 (CCL2 protein, human)
RN  - 0 (CCR2 protein, human)
RN  - 0 (Ccr2 protein, mouse)
RN  - 0 (Ccr2 protein, rat)
RN  - 0 (Chemokine CCL2)
RN  - 0 (Hydroxymethylglutaryl-CoA Reductase Inhibitors)
RN  - 0 (PPAR gamma)
RN  - 0 (Polyisoprenyl Phosphates)
RN  - 0 (RNA, Messenger)
RN  - 0 (Receptors, CCR2)
RN  - 0 (Receptors, Chemokine)
RN  - 0 (Sesquiterpenes)
RN  - 0 (Thiazolidinediones)
RN  - 05V02F2KDG (Rosiglitazone)
RN  - 79W6B01D07 (farnesyl pyrophosphate)
RN  - AGG2FN16EV (Simvastatin)
RN  - N21T0D88LX (geranylgeranyl pyrophosphate)
RN  - S5UOB36OCZ (Mevalonic Acid)
SB  - IM
MH  - Anilides/pharmacology
MH  - Animals
MH  - Aorta/metabolism/pathology
MH  - Cells, Cultured/drug effects/metabolism
MH  - Chemokine CCL2/*metabolism
MH  - Chemotaxis, Leukocyte/*drug effects
MH  - Depression, Chemical
MH  - Diet, Atherogenic
MH  - Down-Regulation/*drug effects
MH  - Drug Evaluation, Preclinical
MH  - Female
MH  - Humans
MH  - Hydroxymethylglutaryl-CoA Reductase Inhibitors/*pharmacology
MH  - Hypercholesterolemia/metabolism/pathology
MH  - Male
MH  - Mevalonic Acid/analysis
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Monocytes/chemistry/*drug effects
MH  - PPAR gamma/antagonists & inhibitors/physiology
MH  - Polyisoprenyl Phosphates/analysis
MH  - RNA, Messenger/biosynthesis
MH  - Rats
MH  - Rats, Sprague-Dawley
MH  - Receptors, CCR2
MH  - Receptors, Chemokine/*biosynthesis/genetics
MH  - Rosiglitazone
MH  - Sesquiterpenes
MH  - Simvastatin/*pharmacology
MH  - Thiazolidinediones/pharmacology
EDAT- 2005/03/23 09:00
MHDA- 2005/09/20 09:00
CRDT- 2005/03/23 09:00
PHST- 2005/03/23 09:00 [pubmed]
PHST- 2005/09/20 09:00 [medline]
PHST- 2005/03/23 09:00 [entrez]
AID - 111/11/1439 [pii]
AID - 10.1161/01.CIR.0000158484.18024.1F [doi]
PST - ppublish
SO  - Circulation. 2005 Mar 22;111(11):1439-47. doi: 
      10.1161/01.CIR.0000158484.18024.1F.