A statin-loaded reconstituted high-density lipoprotein nanoparticle inhibits atherosclerotic plaque inflammation.

Abstract

Inflammation is a key feature of atherosclerosis and a target for therapy. Statins have potent anti-inflammatory properties but these cannot be fully exploited with oral statin therapy due to low systemic bioavailability. Here we present an injectable reconstituted high-density lipoprotein (rHDL) nanoparticle carrier vehicle that delivers statins to atherosclerotic plaques. We demonstrate the anti-inflammatory effect of statin-rHDL in vitro and show that this effect is mediated through the inhibition of the mevalonate pathway. We also apply statin-rHDL nanoparticles in vivo in an apolipoprotein E-knockout mouse model of atherosclerosis and show that they accumulate in atherosclerotic lesions in which they directly affect plaque macrophages. Finally, we demonstrate that a 3-month low-dose statin-rHDL treatment regimen inhibits plaque inflammation progression, while a 1-week high-dose regimen markedly decreases inflammation in advanced atherosclerotic plaques. Statin-rHDL represents a novel potent atherosclerosis nanotherapy that directly affects plaque inflammation.

• Authors: Raphaël Duivenvoorden, Jun Tang, David P Cormode, Aneta J Mieszawska, David Izquierdo-Garcia, Canturk Ozcan, Maarten J Otten, Neeha Zaidi, Mark E Lobatto, Sarian M van Rijs, Bram Priem, Emma L Kuan, Catherine Martel, Bernd Hewing, Hendrik Sager, Matthias Nahrendorf, Gwendalyn J Randolph, Erik S G Stroes, Valentin Fuster, Edward A Fisher, Zahi A Fayad, Willem J M Mulder
• Journal: Nature communications (Nat Commun) Vol. 5 Pg. 3065 ( 2014) ISSN: 2041-1723 [Electronic] England
• PMID: 24445279 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Apolipoproteins E
• Hydroxymethylglutaryl-CoA Reductase Inhibitors
• Lipoproteins, HDL

Topics

• Administration, Intravenous
• Animals
• Apolipoproteins E (deficiency, genetics)
• Disease Models, Animal
• Dose-Response Relationship, Drug
• Hydroxymethylglutaryl-CoA Reductase Inhibitors (administration & dosage, therapeutic use)
• Lipoproteins, HDL (administration & dosage, therapeutic use)
• Male
• Mice
• Mice, Knockout
• Nanoparticles (administration & dosage, therapeutic use)
• Plaque, Atherosclerotic (genetics, prevention & control)
• Treatment Outcome