{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T12:59:52Z","timestamp":1792155592831,"version":"4.4.0"},"reference-count":38,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"3","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["ATVB"],"published-print":{"date-parts":[[2016,3]]},"abstract":"<jats:sec>\n            <jats:title>Objective\u2014<\/jats:title>\n            <jats:p>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\u2013activated receptor-\u03b3 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\u2013activated receptor-\u03b3 agonist pioglitazone into circulating monocytes could effectively inhibit plaque ruptures in a mouse model.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Approach and Results\u2014<\/jats:title>\n            <jats:p>\n              We prepared bioabsorbable poly(lactic-\n              <jats:italic>co<\/jats:italic>\n              -glycolic-acid) nanoparticles containing pioglitazone (pioglitazone-NPs). Intravenously administered poly(lactic-\n              <jats:italic>co<\/jats:italic>\n              -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\n              <jats:italic>ApoE<\/jats:italic>\n              <jats:sup>\n                <jats:italic>\u2212\/\u2212<\/jats:italic>\n              <\/jats:sup>\n              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\u2013derived macrophages.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions\u2014<\/jats:title>\n            <jats:p>\n              Nanoparticle-mediated delivery of pioglitazone inhibited macrophage activation and atherosclerotic plaque ruptures in hyperlipidemic\n              <jats:italic>ApoE<\/jats:italic>\n              <jats:sup>\n                <jats:italic>\u2212\/\u2212<\/jats:italic>\n              <\/jats:sup>\n              mice. These results demonstrate a promising strategy with a favorable safety profile to prevent atherosclerotic plaque ruptures.\n            <\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/atvbaha.115.307057","type":"journal-article","created":{"date-parts":[[2016,1,29]],"date-time":"2016-01-29T04:33:38Z","timestamp":1454042018000},"page":"491-500","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":113,"title":["Pioglitazone-Incorporated Nanoparticles Prevent Plaque Destabilization and Rupture by Regulating Monocyte\/Macrophage Differentiation in\n            <i>ApoE<\/i>\n            <sup>\n              <i>\u2212\/\u2212<\/i>\n            <\/sup>\n            Mice"],"prefix":"10.1161","volume":"36","author":[{"given":"Soichi","family":"Nakashiro","sequence":"first","affiliation":[{"name":"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 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