Abstract 14660: A Nanomedicine-Based Treatment Regimen to Induce Plaque Remodeling to a Favorable Phenotype in Mice With Advanced Atherosclerosis
Rationale: Inflammatory macrophages contribute to an increased chance of atherosclerotic plaque rupture. Previously, we developed a simvastatin loaded high-density lipoprotein ([S]-rHDL) nanoparticle to decrease plaque macrophages in apolipoprotein E-/- (ApoE-/-) mice. In this study, we investigated if a short-term aggressive [S]-rHDL treatment followed by a subsequent mild treatment regimen could induce favorable plaque remodeling.
Results: 99 ApoE-/- mice with advanced atherosclerotic plaques received 4 intravenous (i.v.) doses of [S]-rHDL (60 mg/kg statin, 40 mg/kg ApoA-1) in one week. Subsequently, the mice received either 8-week treatment of oral statin (15 mg/kg/day), low dose [S]-rHDL (15 mg/kg statin, i.v. twice/week) or placebo (A). Macrophage levels (CD68 stain), collagen (trichrome stain) content and plaque size (hematoxylin phloxine saffron stain + CD68 stain) were quantified in aortic root sections. One-week [S]-rHDL treatment resulted in a 68% decrease of macrophage levels (B). Subsequent 8-week oral statin or low dose [S]-rHDL treatment maintained the low macrophage levels (C). Importantly, the collagen/macrophage ratio, an indicator for plaque stability, was significantly higher in these two groups than control (D). Liver, muscle and kidney damage markers were not affected by the treatment. In addition, several molecular biological techniques and in vivo fluorescence molecular tomography imaging were applied to investigate the therapeutic mechanism.
Conclusion: This novel two-pronged nanomedicine/oral statin regimen rapidly reduced macrophage content in advanced atherosclerotic plaques in the first week, while a subsequent moderate 8-week treatment resulted in plaque remodeling towards a high collagen/macrophage ratio. The current nanomedicine-based regimen can potentially induce rapid remodeling to a more favorable plaque phenotype and sustain it over time, which might reduce the risk of recurrent events.
- © 2013 by American Heart Association, Inc.