title: Pioglitazone-Incorporated Nanoparticles Prevent Plaque Destabilization and Rupture by Regulating Monocyte/Macrophage Differentiation in ApoE-/- Mice.
abstract: OBJECTIVE
  Inflammatory monocytes/macrophages produce various proteinases, including matrix metalloproteinases, and degradation of the extracellular matrix by these activated proteinases weakens the mechanical strength of atherosclerotic plaques, which results in a rupture of the plaque. Peroxisome proliferator-activated receptor-γ induces a polarity shift of monocytes/macrophages toward less inflammatory phenotypes and has the potential to prevent atherosclerotic plaque ruptures. Therefore, we hypothesized that nanoparticle-mediated targeted delivery of the peroxisome proliferator-activated receptor-γ agonist pioglitazone into circulating monocytes could effectively inhibit plaque ruptures in a mouse model.
  
  
  RESULTS
  We prepared bioabsorbable poly(lactic-co-glycolic-acid) nanoparticles containing pioglitazone (pioglitazone-NPs). Intravenously administered poly(lactic-co-glycolic-acid) nanoparticles incorporated with fluorescein isothiocyanate were found in circulating monocytes and aortic macrophages by flow cytometric analysis. Weekly intravenous administration of pioglitazone-NPs (7 mg/kg per week) for 4 weeks decreased buried fibrous caps, a surrogate marker of plaque rupture, in the brachiocephalic arteries of ApoE(-/-) mice fed a high-fat diet and infused with angiotensin II. In contrast, administration of control-NPs or an equivalent dose of oral pioglitazone treatment produced no effects. Pioglitazone-NPs inhibited the activity of matrix metalloproteinases and cathepsins in the brachiocephalic arteries. Pioglitazone-NPs regulated inflammatory cytokine expression and also suppressed the expression of extracellular matrix metalloproteinase inducer in bone marrow-derived macrophages.
  
  
  CONCLUSIONS
  Nanoparticle-mediated delivery of pioglitazone inhibited macrophage activation and atherosclerotic plaque ruptures in hyperlipidemic ApoE(-/-) mice. These results demonstrate a promising strategy with a favorable safety profile to prevent atherosclerotic plaque ruptures.
authors.affiliation: From the Departments of Cardiovascular Medicine (S.N., T.M., R.U., J.K., M.T., S.K., K.S.) and Cardiovascular Research, Development, and Translational Medicine (K.N., K.E.), Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan.
authors.forename: Soichi
authors.initials: S
authors.lastname: Nakashiro
authors.affiliation: From the Departments of Cardiovascular Medicine (S.N., T.M., R.U., J.K., M.T., S.K., K.S.) and Cardiovascular Research, Development, and Translational Medicine (K.N., K.E.), Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan. matoba@cardiol.med.kyushu-u.ac.jp.
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Matoba
authors.affiliation: From the Departments of Cardiovascular Medicine (S.N., T.M., R.U., J.K., M.T., S.K., K.S.) and Cardiovascular Research, Development, and Translational Medicine (K.N., K.E.), Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan.
authors.forename: Ryuta
authors.initials: R
authors.lastname: Umezu
authors.affiliation: From the Departments of Cardiovascular Medicine (S.N., T.M., R.U., J.K., M.T., S.K., K.S.) and Cardiovascular Research, Development, and Translational Medicine (K.N., K.E.), Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan.
authors.forename: Jun-Ichiro
authors.initials: J
authors.lastname: Koga
authors.affiliation: From the Departments of Cardiovascular Medicine (S.N., T.M., R.U., J.K., M.T., S.K., K.S.) and Cardiovascular Research, Development, and Translational Medicine (K.N., K.E.), Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan.
authors.forename: Masaki
authors.initials: M
authors.lastname: Tokutome
authors.affiliation: From the Departments of Cardiovascular Medicine (S.N., T.M., R.U., J.K., M.T., S.K., K.S.) and Cardiovascular Research, Development, and Translational Medicine (K.N., K.E.), Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan.
authors.forename: Shunsuke
authors.initials: S
authors.lastname: Katsuki
authors.affiliation: From the Departments of Cardiovascular Medicine (S.N., T.M., R.U., J.K., M.T., S.K., K.S.) and Cardiovascular Research, Development, and Translational Medicine (K.N., K.E.), Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan.
authors.forename: Kaku
authors.initials: K
authors.lastname: Nakano
authors.affiliation: From the Departments of Cardiovascular Medicine (S.N., T.M., R.U., J.K., M.T., S.K., K.S.) and Cardiovascular Research, Development, and Translational Medicine (K.N., K.E.), Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Sunagawa
authors.affiliation: From the Departments of Cardiovascular Medicine (S.N., T.M., R.U., J.K., M.T., S.K., K.S.) and Cardiovascular Research, Development, and Translational Medicine (K.N., K.E.), Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan.
authors.forename: Kensuke
authors.initials: K
authors.lastname: Egashira
mesh_terms: D061605:Administration, Intravenous; D000804:Angiotensin II; D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics; D050197:Atherosclerosis / Q000139:chemically induced / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D016122:Brachiocephalic Trunk / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D002317:Cardiovascular Agents / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D002403:Cathepsins / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects*; D002478:Cells, Cultured; D002626:Chemistry, Pharmaceutical; D016207:Cytokines / Q000378:metabolism; D059305:Diet, High-Fat; D004195:Disease Models, Animal; D018450:Disease Progression; D004337:Drug Carriers; D018836:Inflammation Mediators / Q000378:metabolism; D019344:Lactic Acid / Q000737:chemistry*; D017737:Macrophages, Peritoneal / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008297:Male; D020782:Matrix Metalloproteinases / Q000378:metabolism; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009000:Monocytes / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D053758:Nanoparticles; D010641:Phenotype; D000077205:Pioglitazone; D058226:Plaque, Atherosclerotic; D011100:Polyglycolic Acid / Q000737:chemistry*; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D012422:Rupture, Spontaneous; D045162:Thiazolidinediones / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D001057:Apolipoproteins E; D002317:Cardiovascular Agents; D016207:Cytokines; D004337:Drug Carriers; D018836:Inflammation Mediators; D045162:Thiazolidinediones; D000804:Angiotensin II; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid; D002403:Cathepsins; D020782:Matrix Metalloproteinases; D000077205:Pioglitazone
keywords: macrophages; matrix metalloproteinases; nanoparticles; pioglitazone