Abstract 9601: A Statin-Loaded Nanotherapy Increases Anti-Inflammatory Effects of Statin on Atherosclerosis
Introduction: Statins have a potent cholesterol lowering capability and have shown anti-inflammatory effects, but these effects are limited. We hypothesize that statin-loaded reconstituted high-density lipoprotein nanoparticles ([s]-rHDL) exhibit improved anti-inflammatory effects on atherosclerotic plaques.
Methods & Results: First, we evaluated the targeting of [s]-rHDL in ApoE KO mice with MRI, NIRF imaging, fluorescence microscopy and flow cytometry (n=9). Second, we evaluated the capability of [s]-rHDL to inhibit the progression of atherosclerosis. ApoE KO mice (n=62) were put on a high fat diet and received placebo (n=15), oral Simvastatin (10 mg/kg/day; n=15), intravenous rHDL (10 mg/kg ApoAI twice/week; n=16), or intravenous [s]-rHDL (15 mg/kg Simvastatin, 10 mg/kg ApoAI twice/week; n=16) for 12 weeks. To quantitatively analyze histological sections (n≈4000), an automated procedure was built. Histology results at termination showed that plaque size (hematoxylin phloxine saffron staining) in the [s]-rHDL treated group was significantly reduced compared to rHDL and placebo groups (a). Importantly, the macrophage positive area (anti-CD68 immunostaining) in the [s]-rHDL treated group was profoundly reduced compared to all other groups (b). Third, we assessed the capability of [s]-rHDL to induce rapid regression of atherosclerosis. Mice (n=43) with advanced atherosclerotic plaques were intravenously administered with high dose [s]-rHDL (60 mg/kg Simvastatin, 40 mg/kg ApoAI), low dose [s]-rHDL (15 mg/kg Simvastatin, 10 mg/kg ApoAI), high dose rHDL (60mg/kg ApoAI), or placebo 4 times in one week. One week high dose [s]-rHDL treatment decreased plaque size (c) and almost entirely depleted macrophages in atherosclerotic plaques (d).
Conclusion: [s]-rHDL efficiently targets plaques, thereby improves the anti-inflammatory effects of statins, and can be applied to inhibit plaque progression and induce plaque regression.
- © 2011 by American Heart Association, Inc.