Nanoparticle-mediated delivery of pitavastatin inhibits atherosclerotic plaque destabilization/rupture in mice by regulating the recruitment of inflammatory monocytes

Shunsuke Katsuki, Tetsuya Matoba, Soichi Nakashiro, Kei Sato, Jun Ichiro Koga, Kaku Nakano, Yasuhiro Nakano, Shizuka Egusa, Kenji Sunagawa, Kensuke Egashira

Research output: Contribution to journalArticle

66 Citations (Scopus)

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. 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-6Chigh 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-6GCD11b+ 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.

Original languageEnglish
Pages (from-to)896-906
Number of pages11
JournalCirculation
Volume129
Issue number8
DOIs
Publication statusPublished - Feb 25 2014

Fingerprint

Atherosclerotic Plaques
Nanoparticles
Rupture
Monocytes
Chemokine CCL2
Matrix Metalloproteinase 9
Macrophages
Colony-Stimulating Factors
Gelatinases
Adoptive Transfer
pitavastatin
High Fat Diet
Apolipoproteins E
Chemotaxis
Angiotensin II
Intravenous Administration
Genetic Therapy
Blood Proteins
Leukocytes
Therapeutics

All Science Journal Classification (ASJC) codes

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

Cite this

Nanoparticle-mediated delivery of pitavastatin inhibits atherosclerotic plaque destabilization/rupture in mice by regulating the recruitment of inflammatory monocytes. / Katsuki, Shunsuke; Matoba, Tetsuya; Nakashiro, Soichi; Sato, Kei; Koga, Jun Ichiro; Nakano, Kaku; Nakano, Yasuhiro; Egusa, Shizuka; Sunagawa, Kenji; Egashira, Kensuke.

In: Circulation, Vol. 129, No. 8, 25.02.2014, p. 896-906.

Research output: Contribution to journalArticle

Katsuki, Shunsuke ; Matoba, Tetsuya ; Nakashiro, Soichi ; Sato, Kei ; Koga, Jun Ichiro ; Nakano, Kaku ; Nakano, Yasuhiro ; Egusa, Shizuka ; Sunagawa, Kenji ; Egashira, Kensuke. / Nanoparticle-mediated delivery of pitavastatin inhibits atherosclerotic plaque destabilization/rupture in mice by regulating the recruitment of inflammatory monocytes. In: Circulation. 2014 ; Vol. 129, No. 8. pp. 896-906.
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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. 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-6Chigh 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-6GCD11b+ 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.",
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T1 - Nanoparticle-mediated delivery of pitavastatin inhibits atherosclerotic plaque destabilization/rupture in mice by regulating the recruitment of inflammatory monocytes

AU - Katsuki, Shunsuke

AU - Matoba, Tetsuya

AU - Nakashiro, Soichi

AU - Sato, Kei

AU - Koga, Jun Ichiro

AU - Nakano, Kaku

AU - Nakano, Yasuhiro

AU - Egusa, Shizuka

AU - Sunagawa, Kenji

AU - Egashira, Kensuke

PY - 2014/2/25

Y1 - 2014/2/25

N2 - 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. 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-6Chigh 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-6GCD11b+ 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.

AB - 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. 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-6Chigh 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-6GCD11b+ 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.

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