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Nanoparticle-mediated delivery of pitavastatin inhibits atherosclerotic plaque destabilization/rupture in mice by regulating the recruitment of inflammatory monocytes.
- Source :
-
Circulation [Circulation] 2014 Feb 25; Vol. 129 (8), pp. 896-906. Date of Electronic Publication: 2013 Dec 04. - Publication Year :
- 2014
-
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.<br />Methods and 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.<br />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.
- Subjects :
- Adoptive Transfer
Animals
Apolipoproteins E genetics
Brachiocephalic Trunk drug effects
Brachiocephalic Trunk immunology
Brachiocephalic Trunk pathology
Cell Movement drug effects
Cell Movement immunology
Chemokine CCL2 antagonists & inhibitors
Chemokine CCL2 metabolism
Disease Models, Animal
Genetic Therapy methods
Hydroxymethylglutaryl-CoA Reductase Inhibitors pharmacokinetics
Male
Mice
Mice, 129 Strain
Mice, Inbred C57BL
Mice, Knockout
Monocytes immunology
Monocytes pathology
Nanoparticles therapeutic use
Plaque, Atherosclerotic immunology
Plaque, Atherosclerotic pathology
Receptors, CCR2 genetics
Drug Delivery Systems methods
Monocytes drug effects
Nanoparticles metabolism
Plaque, Atherosclerotic drug therapy
Quinolines pharmacokinetics
Subjects
Details
- Language :
- English
- ISSN :
- 1524-4539
- Volume :
- 129
- Issue :
- 8
- Database :
- MEDLINE
- Journal :
- Circulation
- Publication Type :
- Academic Journal
- Accession number :
- 24305567
- Full Text :
- https://doi.org/10.1161/CIRCULATIONAHA.113.002870