HMG-CoA reductase inhibition reduces monocyte CC chemokine receptor 2 expression and monocyte chemoattractant protein-1-mediated monocyte recruitment in vivo.
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.
Han
Ki Hoon
KH
Asan Medical Center, University of Ulsan, College of Medicine, Seoul, Korea. steadyhan@amc.seoul.kr
Ryu
Jewon
J
Hong
Kyung Hee
KH
Ko
Jesang
J
Pak
Youngmi Kim
YK
Kim
Jae-Bum
JB
Park
Seong Wook
SW
Kim
Jae Joong
JJ
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
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