title: Nanoparticle-mediated delivery of pitavastatin inhibits atherosclerotic plaque destabilization/rupture in mice by regulating the recruitment of inflammatory monocytes.
abstract: BACKGROUND
  Preventing atherosclerotic plaque destabilization and rupture is the most reasonable therapeutic strategy for acute myocardial infarction. Therefore, we tested the hypotheses that (1) inflammatory monocytes play a causative role in plaque destabilization and rupture and (2) the nanoparticle-mediated delivery of pitavastatin into circulating inflammatory monocytes inhibits plaque destabilization and rupture.
  
  
  RESULTS
  We used a model of plaque destabilization and rupture in the brachiocephalic arteries of apolipoprotein E-deficient (ApoE(-/-)) mice fed a high-fat diet and infused with angiotensin II. The adoptive transfer of CCR2(+/+)Ly-6C(high) inflammatory macrophages, but not CCR2(-/-) leukocytes, accelerated plaque destabilization associated with increased serum monocyte chemoattractant protein-1 (MCP-1), monocyte-colony stimulating factor, and matrix metalloproteinase-9. We prepared poly(lactic-co-glycolic) acid nanoparticles that were incorporated by Ly-6G(-)CD11b(+) monocytes and delivered into atherosclerotic plaques after intravenous administration. Intravenous treatment with pitavastatin-incorporated nanoparticles, but not with control nanoparticles or pitavastatin alone, inhibited plaque destabilization and rupture associated with decreased monocyte infiltration and gelatinase activity in the plaque. Pitavastatin-incorporated nanoparticles inhibited MCP-1-induced monocyte chemotaxis and the secretion of MCP-1 and matrix metalloproteinase-9 from cultured macrophages. Furthermore, the nanoparticle-mediated anti-MCP-1 gene therapy reduced the incidence of plaque destabilization and rupture.
  
  
  CONCLUSIONS
  The recruitment of inflammatory monocytes is critical in the pathogenesis of plaque destabilization and rupture, and nanoparticle-mediated pitavastatin delivery is a promising therapeutic strategy to inhibit plaque destabilization and rupture by regulating MCP-1/CCR2-dependent monocyte recruitment in this model.
authors.affiliation: Department of Cardiovascular Medicine (S.K., T.M., S.N., J.K., Y.N., S.E., K. Sunagawa) and Department of Cardiovascular Research, Development, and Translational Medicine (K. Sato, K.N., K.E.), Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan.
authors.forename: Shunsuke
authors.initials: S
authors.lastname: Katsuki
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Matoba
authors.forename: Soichi
authors.initials: S
authors.lastname: Nakashiro
authors.forename: Kei
authors.initials: K
authors.lastname: Sato
authors.forename: Jun-ichiro
authors.initials: J
authors.lastname: Koga
authors.forename: Kaku
authors.initials: K
authors.lastname: Nakano
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Nakano
authors.forename: Shizuka
authors.initials: S
authors.lastname: Egusa
authors.forename: Kenji
authors.initials: K
authors.lastname: Sunagawa
authors.forename: Kensuke
authors.initials: K
authors.lastname: Egashira
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics; D016122:Brachiocephalic Trunk / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D002465:Cell Movement / Q000187:drug effects / Q000276:immunology; D018932:Chemokine CCL2 / Q000037:antagonists & inhibitors / Q000378:metabolism; D004195:Disease Models, Animal; D016503:Drug Delivery Systems / Q000379:methods*; D015316:Genetic Therapy / Q000379:methods; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000493:pharmacokinetics; D008297:Male; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009000:Monocytes / Q000187:drug effects* / Q000276:immunology / Q000473:pathology; D053758:Nanoparticles / Q000378:metabolism* / Q000627:therapeutic use; D058226:Plaque, Atherosclerotic / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D011804:Quinolines / Q000493:pharmacokinetics*; D054390:Receptors, CCR2 / Q000235:genetics
chemical_list: D001057:Apolipoproteins E; C491768:Ccl2 protein, mouse; C515335:Ccr2 protein, mouse; D018932:Chemokine CCL2; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011804:Quinolines; D054390:Receptors, CCR2; C108475:pitavastatin
keywords: monocytes; myocardial infarction; nanoparticles; plaque; statins, HMG-CoA