Majmudar, Maulik D.Keliher, Edmund J.Heidt, TimoLeuschner, FlorianTruelove, JessicaSena, Brena F.Gorbatov, RosticIwamoto, YoshikoDutta, ParthaWojtkiewicz, GregoryCourties, GabrielSebas, MattBorodovsky, AnnaFitzgerald, KevinNolte, Marc W.Dickneite, GerhardChen, John W.Anderson, Daniel G.Swirski, Filip K.Weissleder, RalphNahrendorf, Matthias2019-09-212013Majmudar, Maulik D., Edmund J. Keliher, Timo Heidt, Florian Leuschner, Jessica Truelove, Brena F. Sena, Rostic Gorbatov, et al. 2013. “Monocyte-Directed RNAi Targeting CCR2 Improves Infarct Healing in Atherosclerosis-Prone Mice.” Circulation 127 (20): 2038–46. https://doi.org/10.1161/circulationaha.112.000116.0009-73220069-41931524-4539http://nrs.harvard.edu/urn-3:HUL.InstRepos:41384203Background-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. Methods: and 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 (F-18-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 F-18-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). Conclusion- CCR2-targeted RNAi reduced recruitment of Ly-6C(high) monocytes, attenuated infarct inflammation, and curbed post-MI left ventricular remodeling.en-USJournal Article2019-09-2110.1161/CIRCULATIONAHA.112.000116