title: Inhibiting macrophage proliferation suppresses atherosclerotic plaque inflammation.
abstract: Inflammation drives atherosclerotic plaque progression and rupture, and is a compelling therapeutic target. Consequently, attenuating inflammation by reducing local macrophage accumulation is an appealing approach. This can potentially be accomplished by either blocking blood monocyte recruitment to the plaque or increasing macrophage apoptosis and emigration. Because macrophage proliferation was recently shown to dominate macrophage accumulation in advanced plaques, locally inhibiting macrophage proliferation may reduce plaque inflammation and produce long-term therapeutic benefits. To test this hypothesis, we used nanoparticle-based delivery of simvastatin to inhibit plaque macrophage proliferation in apolipoprotein E deficient mice (Apoe-/-) with advanced atherosclerotic plaques. This resulted in rapid reduction of plaque inflammation and favorable phenotype remodeling. We then combined this short-term nanoparticle intervention with an eight-week oral statin treatment, and this regimen rapidly reduced and continuously suppressed plaque inflammation. Our results demonstrate that pharmacologically inhibiting local macrophage proliferation can effectively treat inflammation in atherosclerosis.
authors: Translational and Molecular Imaging Institute, Icahn School of Medicine at Mount Sinai, New York 10029, NY, USA ; Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors: Jun
authors: J
authors: Tang
authors: Translational and Molecular Imaging Institute, Icahn School of Medicine at Mount Sinai, New York 10029, NY, USA ; Department of Vascular Medicine, Academic Medical Center, Amsterdam 1105 AZ, The Netherlands.
authors: Mark E
authors: ME
authors: Lobatto
authors: Translational and Molecular Imaging Institute, Icahn School of Medicine at Mount Sinai, New York 10029, NY, USA ; Department of Vascular Medicine, Academic Medical Center, Amsterdam 1105 AZ, The Netherlands.
authors: Laurien
authors: L
authors: Hassing
authors: Translational and Molecular Imaging Institute, Icahn School of Medicine at Mount Sinai, New York 10029, NY, USA ; Department of Vascular Medicine, Academic Medical Center, Amsterdam 1105 AZ, The Netherlands.
authors: Susanne
authors: S
authors: van der Staay
authors: Translational and Molecular Imaging Institute, Icahn School of Medicine at Mount Sinai, New York 10029, NY, USA ; Department of Vascular Medicine, Academic Medical Center, Amsterdam 1105 AZ, The Netherlands.
authors: Sarian M
authors: SM
authors: van Rijs
authors: Translational and Molecular Imaging Institute, Icahn School of Medicine at Mount Sinai, New York 10029, NY, USA.
authors: Claudia
authors: C
authors: Calcagno
authors: Translational and Molecular Imaging Institute, Icahn School of Medicine at Mount Sinai, New York 10029, NY, USA.
authors: Mounia S
authors: MS
authors: Braza
authors: Translational and Molecular Imaging Institute, Icahn School of Medicine at Mount Sinai, New York 10029, NY, USA.
authors: Samantha
authors: S
authors: Baxter
authors: Translational and Molecular Imaging Institute, Icahn School of Medicine at Mount Sinai, New York 10029, NY, USA.
authors: Francois
authors: F
authors: Fay
authors: Translational and Molecular Imaging Institute, Icahn School of Medicine at Mount Sinai, New York 10029, NY, USA.
authors: Brenda L
authors: BL
authors: Sanchez-Gaytan
authors: Department of Vascular Medicine, Academic Medical Center, Amsterdam 1105 AZ, The Netherlands.
authors: Raphaël
authors: R
authors: Duivenvoorden
authors: Center for Systems Biology, Massachusetts General Hospital, and Division of Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02114, USA.
authors: Hendrik
authors: H
authors: Sager
authors: Department of Medicine (Cardiology) and Cell Biology, Marc and Ruti Bell Program in Vascular Biology, NYU School of Medicine, New York, NY 10016, USA.
authors: Yaritzy M
authors: YM
authors: Astudillo
authors: Translational and Molecular Imaging Institute, Icahn School of Medicine at Mount Sinai, New York 10029, NY, USA ; Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors: Wei
authors: W
authors: Leong
authors: Translational and Molecular Imaging Institute, Icahn School of Medicine at Mount Sinai, New York 10029, NY, USA.
authors: Sarayu
authors: S
authors: Ramachandran
authors: Department of Pharmaceutics, Utrecht Institute of Pharmaceutical Sciences, Utrecht University, Universiteitsweg 99, 3584 CG Utrecht, The Netherlands ; Department of Controlled Drug Delivery, MIRA Institute for Biomedical Engineering and Technical Medicine, University of Twente, 7500 AE Enschede, The Netherlands.
authors: Gert
authors: G
authors: Storm
authors: Translational and Molecular Imaging Institute, Icahn School of Medicine at Mount Sinai, New York 10029, NY, USA.
authors: Carlos
authors: C
authors: Pérez-Medina
authors: Department of Radiology, Memorial Sloan-Kettering Cancer Center, 1275 York Ave., New York, NY 10065.
authors: Thomas
authors: T
authors: Reiner
authors: Department of Radiology, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors: David P
authors: DP
authors: Cormode
authors: Department of Biomedical Engineering and Physics, Academic Medical Center, Amsterdam, The Netherlands.
authors: Gustav J
authors: GJ
authors: Strijkers
authors: Department of Vascular Medicine, Academic Medical Center, Amsterdam 1105 AZ, The Netherlands.
authors: Erik S G
authors: ES
authors: Stroes
authors: Center for Systems Biology, Massachusetts General Hospital, and Division of Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02114, USA.
authors: Filip K
authors: FK
authors: Swirski
authors: Center for Systems Biology, Massachusetts General Hospital, and Division of Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02114, USA.
authors: Matthias
authors: M
authors: Nahrendorf
authors: Department of Medicine (Cardiology) and Cell Biology, Marc and Ruti Bell Program in Vascular Biology, NYU School of Medicine, New York, NY 10016, USA.
authors: Edward A
authors: EA
authors: Fisher
authors: Translational and Molecular Imaging Institute, Icahn School of Medicine at Mount Sinai, New York 10029, NY, USA.
authors: Zahi A
authors: ZA
authors: Fayad
authors: Translational and Molecular Imaging Institute, Icahn School of Medicine at Mount Sinai, New York 10029, NY, USA ; Department of Vascular Medicine, Academic Medical Center, Amsterdam 1105 AZ, The Netherlands.
authors: Willem J M
authors: WJ
authors: Mulder