title: Monocyte-directed RNAi targeting CCR2 improves infarct healing in atherosclerosis-prone mice.
abstract: BACKGROUND
  Exaggerated and prolonged inflammation after myocardial infarction (MI) accelerates left ventricular remodeling. Inflammatory pathways may present a therapeutic target to prevent post-MI heart failure. However, the appropriate magnitude and timing of interventions are largely unknown, in part because noninvasive monitoring tools are lacking. Here, we used nanoparticle-facilitated silencing of CCR2, the chemokine receptor that governs inflammatory Ly-6C(high) monocyte subset traffic, to reduce infarct inflammation in apolipoprotein E-deficient (apoE(-/-)) mice after MI. We used dual-target positron emission tomography/magnetic resonance imaging of transglutaminase factor XIII (FXIII) and myeloperoxidase (MPO) activity to monitor how monocyte subset-targeted RNAi altered infarct inflammation and healing.
  
  
  RESULTS
  Flow cytometry, gene expression analysis, and histology revealed reduced monocyte numbers and enhanced resolution of inflammation in infarcted hearts of apoE(-/-) mice that were treated with nanoparticle-encapsulated siRNA. To follow extracellular matrix cross-linking noninvasively, we developed a fluorine-18-labeled positron emission tomography agent ((18)F-FXIII). Recruitment of MPO-rich inflammatory leukocytes was imaged with a molecular magnetic resonance imaging sensor of MPO activity (MPO-Gd). Positron emission tomography/magnetic resonance imaging detected anti-inflammatory effects of intravenous nanoparticle-facilitated siRNA therapy (75% decrease of MPO-Gd signal; P<0.05), whereas (18)F-FXIII positron emission tomography reflected unimpeded matrix cross-linking in the infarct. Silencing of CCR2 during the first week after MI improved ejection fraction on day 21 after MI from 29% to 35% (P<0.05).
  
  
  CONCLUSIONS
  CCR2-targeted RNAi reduced recruitment of Ly-6C(high) monocytes, attenuated infarct inflammation, and curbed post-MI left ventricular remodeling.
authors.affiliation: Center for Systems Biology, Massachusetts General Hospital, 185 Cambridge St, Boston, MA 02114, USA. mnahrendorf@mgh.harvard.edu
authors.forename: Maulik D
authors.initials: MD
authors.lastname: Majmudar
authors.forename: Edmund J
authors.initials: EJ
authors.lastname: Keliher
authors.forename: Timo
authors.initials: T
authors.lastname: Heidt
authors.forename: Florian
authors.initials: F
authors.lastname: Leuschner
authors.forename: Jessica
authors.initials: J
authors.lastname: Truelove
authors.forename: Brena F
authors.initials: BF
authors.lastname: Sena
authors.forename: Rostic
authors.initials: R
authors.lastname: Gorbatov
authors.forename: Yoshiko
authors.initials: Y
authors.lastname: Iwamoto
authors.forename: Partha
authors.initials: P
authors.lastname: Dutta
authors.forename: Gregory
authors.initials: G
authors.lastname: Wojtkiewicz
authors.forename: Gabriel
authors.initials: G
authors.lastname: Courties
authors.forename: Matt
authors.initials: M
authors.lastname: Sebas
authors.forename: Anna
authors.initials: A
authors.lastname: Borodovsky
authors.forename: Kevin
authors.initials: K
authors.lastname: Fitzgerald
authors.forename: Marc W
authors.initials: MW
authors.lastname: Nolte
authors.forename: Gerhard
authors.initials: G
authors.lastname: Dickneite
authors.forename: John W
authors.initials: JW
authors.lastname: Chen
authors.forename: Daniel G
authors.initials: DG
authors.lastname: Anderson
authors.forename: Filip K
authors.initials: FK
authors.lastname: Swirski
authors.forename: Ralph
authors.initials: R
authors.lastname: Weissleder
authors.forename: Matthias
authors.initials: M
authors.lastname: Nahrendorf
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D050197:Atherosclerosis / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D005260:Female; D018390:Gene Targeting / Q000379:methods*; D020022:Genetic Predisposition to Disease; D015316:Genetic Therapy / Q000379:methods; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D009000:Monocytes / Q000378:metabolism* / Q000473:pathology; D009203:Myocardial Infarction / Q000235:genetics* / Q000473:pathology / Q000628:therapy*; D034622:RNA Interference / Q000502:physiology*; D011897:Random Allocation; D054390:Receptors, CCR2 / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D014945:Wound Healing / Q000235:genetics*
chemical_list: C515335:Ccr2 protein, mouse; D054390:Receptors, CCR2
keywords: RNA, small interfering; heart failure; inflammation; magnetic resonance imaging; molecular imaging; monocytes; myocardial infarction; positron-emission tomography; ventricular remodeling