A statin-loaded reconstituted high-density lipoprotein nanoparticle inhibits atherosclerotic plaque inflammation.
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.
1] Translational and Molecular Imaging Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA [2] Department of Vascular Medicine, Academic Medical Center, Amsterdam 1105 AZ, The Netherlands [3].
Raphaël
R
Duivenvoorden
1] Translational and Molecular Imaging Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA [2] Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA [3].
Jun
J
Tang
1] Translational and Molecular Imaging Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA [2].
David P
DP
Cormode
Translational and Molecular Imaging Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA.
Aneta J
AJ
Mieszawska
Translational and Molecular Imaging Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA.
David
D
Izquierdo-Garcia
Translational and Molecular Imaging Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA.
Canturk
C
Ozcan
Translational and Molecular Imaging Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA.
Maarten J
MJ
Otten
Translational and Molecular Imaging Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA.
Neeha
N
Zaidi
1] Translational and Molecular Imaging Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA [2] Department of Vascular Medicine, Academic Medical Center, Amsterdam 1105 AZ, The Netherlands.
Mark E
ME
Lobatto
Translational and Molecular Imaging Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA.
Sarian M
SM
van Rijs
Translational and Molecular Imaging Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA.
Bram
B
Priem
Department of Gene and Cell Medicine, Institute for Immunology, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA.
Emma L
EL
Kuan
Department of Pathology and Immunology, Washington University in St Louis, St Louis, Missouri 63110, USA.
Catherine
C
Martel
1] Department of Medicine (Cardiology) and Cell Biology, Marc and Ruti Bell Program in Vascular Biology, NYU School of Medicine, New York, New York 10016, USA [2] Medizinische Klinik für Kardiologie und Angiologie, Campus Mitte, Charité-Universitaetsmedizin Berlin, Berlin 10117, Germany.
Bernd
B
Hewing
Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Simches Research Building, 185 Cambridge Street, Boston, Massachusetts 02114, USA.
Hendrik
H
Sager
Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Simches Research Building, 185 Cambridge Street, Boston, Massachusetts 02114, USA.
Matthias
M
Nahrendorf
Department of Pathology and Immunology, Washington University in St Louis, St Louis, Missouri 63110, USA.
Gwendalyn J
GJ
Randolph
Department of Vascular Medicine, Academic Medical Center, Amsterdam 1105 AZ, The Netherlands.
Erik S G
ES
Stroes
1] Department of Cardiology, Marie-Josée and Henry R. Kravis Cardiovascular Health Center, Zena and Michael A. Weiner Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, New York, New York, 10029, USA [2] Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid 28029, Spain.
Valentin
V
Fuster
Medizinische Klinik für Kardiologie und Angiologie, Campus Mitte, Charité-Universitaetsmedizin Berlin, Berlin 10117, Germany.
Edward A
EA
Fisher
Translational and Molecular Imaging Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA.
Zahi A
ZA
Fayad
1] Translational and Molecular Imaging Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA [2] Department of Vascular Medicine, Academic Medical Center, Amsterdam 1105 AZ, The Netherlands.
Willem J M
WJ
Mulder
D061605:Administration, Intravenous; D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000008:administration & dosage / Q000627:therapeutic use*; D008075:Lipoproteins, HDL / Q000008:administration & dosage / Q000627:therapeutic use*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D053758:Nanoparticles / Q000008:administration & dosage / Q000627:therapeutic use*; D058226:Plaque, Atherosclerotic / Q000235:genetics / Q000517:prevention & control*; D016896:Treatment Outcome
D001057:Apolipoproteins E; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008075:Lipoproteins, HDL