Monocyte-Directed RNAi Targeting CCR2 Improves Infarct Healing in Atherosclerosis-Prone Mice
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...
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| Format: | Article |
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American Heart Association
2014
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| Online Access: | http://hdl.handle.net/1721.1/91250 https://orcid.org/0000-0001-5629-4798 |
| _version_ | 1826207150045659136 |
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| author | Majmudar, Maulik D. Keliher, Edmund J. Heidt, Timo Leuschner, Florian Truelove, Jessica Sena, Brena F. Gorbatov, Rostic Iwamoto, Yoshiko Dutta, Partha Wojtkiewicz, Gregory Courties, Gabriel Sebas, Matt Borodovsky, Anna Fitzgerald, Kevin Nolte, Marc W. Dickneite, Gerhard Chen, John W. Anderson, Daniel Griffith Swirski, Filip K. Weissleder, Ralph Nahrendorf, Matthias |
| author2 | Harvard University--MIT Division of Health Sciences and Technology |
| author_facet | Harvard University--MIT Division of Health Sciences and Technology Majmudar, Maulik D. Keliher, Edmund J. Heidt, Timo Leuschner, Florian Truelove, Jessica Sena, Brena F. Gorbatov, Rostic Iwamoto, Yoshiko Dutta, Partha Wojtkiewicz, Gregory Courties, Gabriel Sebas, Matt Borodovsky, Anna Fitzgerald, Kevin Nolte, Marc W. Dickneite, Gerhard Chen, John W. Anderson, Daniel Griffith Swirski, Filip K. Weissleder, Ralph Nahrendorf, Matthias |
| author_sort | Majmudar, Maulik D. |
| collection | MIT |
| description | 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-6Chigh 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 (18F-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 18F-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-6Chigh monocytes, attenuated infarct inflammation, and curbed post-MI left ventricular remodeling. |
| first_indexed | 2024-09-23T13:44:49Z |
| format | Article |
| id | mit-1721.1/91250 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T13:44:49Z |
| publishDate | 2014 |
| publisher | American Heart Association |
| record_format | dspace |
| spelling | mit-1721.1/912502022-09-28T15:52:48Z Monocyte-Directed RNAi Targeting CCR2 Improves Infarct Healing in Atherosclerosis-Prone Mice Majmudar, Maulik D. Keliher, Edmund J. Heidt, Timo Leuschner, Florian Truelove, Jessica Sena, Brena F. Gorbatov, Rostic Iwamoto, Yoshiko Dutta, Partha Wojtkiewicz, Gregory Courties, Gabriel Sebas, Matt Borodovsky, Anna Fitzgerald, Kevin Nolte, Marc W. Dickneite, Gerhard Chen, John W. Anderson, Daniel Griffith Swirski, Filip K. Weissleder, Ralph Nahrendorf, Matthias Harvard University--MIT Division of Health Sciences and Technology Massachusetts Institute of Technology. Department of Chemical Engineering Koch Institute for Integrative Cancer Research at MIT Anderson, Daniel Griffith 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-6Chigh 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 (18F-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 18F-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-6Chigh monocytes, attenuated infarct inflammation, and curbed post-MI left ventricular remodeling. National Heart, Lung, and Blood Institute United States. Dept. of Health and Human Services (contract No. HHSN268201000044C) National Institutes of Health (U.S.) (grant R01-HL096576) National Institutes of Health (U.S.) (grant R01-HL095629) National Institutes of Health (U.S.) (grant T32-HL094301) Deutsche Forschungsgemeinschaft (HE-6382/1-1) 2014-10-31T16:27:27Z 2014-10-31T16:27:27Z 2013-04 2012-11 Article http://purl.org/eprint/type/JournalArticle 0009-7322 1524-4539 http://hdl.handle.net/1721.1/91250 Majmudar, M. D., E. J. Keliher, T. Heidt, F. Leuschner, J. Truelove, B. F. Sena, R. Gorbatov, et al. “Monocyte-Directed RNAi Targeting CCR2 Improves Infarct Healing in Atherosclerosis-Prone Mice.” Circulation 127, no. 20 (April 24, 2013): 2038–2046. https://orcid.org/0000-0001-5629-4798 en_US http://dx.doi.org/10.1161/circulationaha.112.000116 Circulation Creative Commons Attribution-Noncommercial-Share Alike http://creativecommons.org/licenses/by-nc-sa/4.0/ application/pdf American Heart Association PMC |
| spellingShingle | Majmudar, Maulik D. Keliher, Edmund J. Heidt, Timo Leuschner, Florian Truelove, Jessica Sena, Brena F. Gorbatov, Rostic Iwamoto, Yoshiko Dutta, Partha Wojtkiewicz, Gregory Courties, Gabriel Sebas, Matt Borodovsky, Anna Fitzgerald, Kevin Nolte, Marc W. Dickneite, Gerhard Chen, John W. Anderson, Daniel Griffith Swirski, Filip K. Weissleder, Ralph Nahrendorf, Matthias Monocyte-Directed RNAi Targeting CCR2 Improves Infarct Healing in Atherosclerosis-Prone Mice |
| title | Monocyte-Directed RNAi Targeting CCR2 Improves Infarct Healing in Atherosclerosis-Prone Mice |
| title_full | Monocyte-Directed RNAi Targeting CCR2 Improves Infarct Healing in Atherosclerosis-Prone Mice |
| title_fullStr | Monocyte-Directed RNAi Targeting CCR2 Improves Infarct Healing in Atherosclerosis-Prone Mice |
| title_full_unstemmed | Monocyte-Directed RNAi Targeting CCR2 Improves Infarct Healing in Atherosclerosis-Prone Mice |
| title_short | Monocyte-Directed RNAi Targeting CCR2 Improves Infarct Healing in Atherosclerosis-Prone Mice |
| title_sort | monocyte directed rnai targeting ccr2 improves infarct healing in atherosclerosis prone mice |
| url | http://hdl.handle.net/1721.1/91250 https://orcid.org/0000-0001-5629-4798 |
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