Abstract 13315: Nanoparticle-Mediated Monocyte-Selective Delivery of Pitavastatin Prevents Angiotensin II-Induced Abdominal Aortic Aneurysm Formation in ApoE-Deficient Mice
Background: Abdominal aortic aneurysm (AAA) is a common disease and lethal when it progresses to rupture, but current medical treatments are insufficient to suppress AAA progression. Recent studies suggest a key role of monocyte-related inflammation in the pathogenesis of AAA.
Hypothesis: Nanoparticle (NP)-mediated monocyte-selective delivery of pitavastatin (Pitava) effectively ameliorates the development of AAA in a murine model.
Methods and Results: We prepared bioabsorbable PLGA-NPs, which were incorporated into CD11b+ monocytes and then delivered into the abdominal aorta after intravenous injection. In cultured monocytes, Pitava-NP inhibited lipopolysaccaride-induced NF-κB activation and MCP-1 gene expression. To examine therapeutic effects of Pitava-NP, we used a murine model of AAA in ApoE-deficient mice fed with high-fat diet and infused with angiotensin II. Treatment with Pitava-NP (weekly intravenous injection of NP containing 0.4 mg/kg Pitava for 4 weeks), but not that with control FITC-NP or Pitava alone, prevented the AAA formation (5/9 vs 0/11 for FITC-NP and Pitava-NP), partly attenuated the development of rupture, reduced monocyte recruitment and MCP-1 expression in AAA sites (Figure), and reduced serum MCP-1 levels. Importantly, the AAA formation was markedly blunted in ApoE/CCR2 (a receptor of MCP-1)-double deficient mice and the mice treated with NP containing dominant-negative inhibitor of MCP−1. In contrast, no such beneficial effects were seen in other groups treated with oral administration of Pitava at 1 and 10 mg/kg per day for 4 weeks.
Conclusion: NP-mediated monocyte-selective delivery of Pitava is more effective in inhibiting AAA formation and rupture compared with systemic administration of Pitava. The therapeutic effect of Pitava-NP was mediated mainly by monocyte-related inflammation through the MCP-1 pathway. This NP delivery system may be developed as a new therapy for the AAA progression and rupture.
- © 2010 by American Heart Association, Inc.