Abstract 12884: Nanoparticle-Mediated Delivery of Pitavastatin Inhibits Plaque Destabilization and Rupture in the Brachiocephalic Arteries of ApoE-Deficient Mice through Regulating Monocyte Activation
Prevention of atherosclerotic plaque destabilization and rupture is the most reasonable therapeutic strategy for acute myocardial infarction (AMI). Therefore, we tested the hypothesis that (i) monocyte activation plays a key role in causing plaque destabilization and rupture; and (ii) nanoparticle (NP)-mediated delivery of pitavastatin inhibits plaque destabilization and rupture by inhibiting monocyte activation. We used a model of plaque destabilization and rupture in the brachiocephalic arteries of ApoE-/- mice fed with high-fat diet and infused with angiotensin II. Adoptive-transfer of inflammatory activated monocyte accelerated plaque destabilization and rupture associated with increased markers of monocyte activation. We then prepared polymeric-NPs, which were uptaken by CD11b+ monocytes and delivered into atherosclerotic plaques after intravenous administration. The NP-mediated blockade of MCP-1/CCR2 pathway in monocytes by dominant negative inhibitor of MCP-1 reduced the incidence of plaque destabilization and rupture. Intravenous treatment with pitavastatin-NP, but not that with control-NP or pitavastatin, inhibited plaque destabilization and rupture associated with decreased monocyte infiltration/activation (Figure A). Pitavastatin-NP, but not control-NP, also inhibited monocyte activation in the peripheral blood (Figure B) and gelatinase activity in the atherosclerotic plaques (Figure C). In conclusions, monocyte activation is critical in the pathogenesis of plaque destabilization and rupture, and this mode of NP-mediated pitavastatin delivery inhibited plaque destabilization and rupture regulating monocyte activation in this model. This nanotechnology-based modality can be developed as a new therapeutic strategy to prevent AMI in the future.
- © 2012 by American Heart Association, Inc.