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dc.contributor.authorLuo, Jun
dc.contributor.authorWeaver, Matthew S.
dc.contributor.authorFitzgibbons, Timothy P.
dc.contributor.authorAouadi, Myriam
dc.contributor.authorCzech, Michael P.
dc.contributor.authorAllen, Margaret D.
dc.date2022-08-11T08:09:58.000
dc.date.accessioned2022-08-23T16:50:40Z
dc.date.available2022-08-23T16:50:40Z
dc.date.issued2020-12-02
dc.date.submitted2021-02-05
dc.identifier.citation<p>Luo J, Weaver MS, Fitzgibbons TP, Aouadi M, Czech MP, Allen MD. Immunotherapy for Infarcts: <em>In Vivo</em> Postinfarction Macrophage Modulation Using Intramyocardial Microparticle Delivery of <em>Map4k4</em> Small Interfering RNA. Biores Open Access. 2020 Dec 2;9(1):258-268. doi: 10.1089/biores.2020.0037. PMID: 33376632; PMCID: PMC7757732. <a href="https://doi.org/10.1089/biores.2020.0037">Link to article on publisher's site</a></p>
dc.identifier.issn2164-7844 (Linking)
dc.identifier.doi10.1089/biores.2020.0037
dc.identifier.pmid33376632
dc.identifier.urihttp://hdl.handle.net/20.500.14038/41702
dc.description.abstractThe myeloid cells infiltrating the heart early after acute myocardial infarction elaborate a secretome that largely orchestrates subsequent ventricular wall repair. Regulating this innate immune response could be a means to improve infarct healing. To pilot this concept, we utilized (beta1,3-d-) glucan-encapsulated small interfering RNA (siRNA)-containing particles (GeRPs), targeting mononuclear phagocytes, delivered to mice as a one-time intramyocardial injection immediately after acute infarction. Findings demonstrated that cardiac macrophages phagocytosed GeRPs in vivo and had little systemic dissemination, thus providing a means to deliver local therapeutics. Acute infarcts were then injected in vivo with phosphate-buffered saline (PBS; vehicle) or GeRPs loaded with siRNA to Map4k4, and excised hearts were examined at 3 and 7 days by quantitative polymerase chain reaction, flow cytometry, and histology. Compared with infarcted PBS-treated hearts, hearts with intrainfarct injections of siRNA-loaded GeRPs exhibited 69-89% reductions in transcripts for Map4k4 (mitogen-activated protein kinase kinase kinase kinase 4), interleukin (IL)-1beta, and tumor necrosis factor alpha at 3 days. Expression of other factors relevant to matrix remodeling-monocyte chemoattractant protein-1 (MCP-1), matrix metalloproteinases, hyaluronan synthases, matricellular proteins, and profibrotic factors transforming growth factor beta (TGF-beta), and connective tissue growth factor (CTGF)-were also decreased. Most effects peaked at 3 days, but, in some instances (Map4k4, IL-1beta, TGF-beta, CTGF, versican, and periostin), suppression persisted to 7 days. Thus, direct intramyocardial GeRP injection could serve as a novel and clinically translatable platform for in vivo RNA delivery to intracardiac macrophages for local and selective immunomodulation of the infarct microenvironment.
dc.language.isoen_US
dc.relation<p><a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&list_uids=33376632&dopt=Abstract">Link to Article in PubMed</a></p>
dc.rightsCopyright Jun Luo et al., 2020; Published by Mary Ann Liebert, Inc. This Open Access article is distributed under the terms of the Creative Commons License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/
dc.subjectMap4k4
dc.subjectintramyocardial
dc.subjectmacrophage
dc.subjectmicroparticle
dc.subjectmyocardial infarction
dc.subjectsiRNA
dc.subjectCardiology
dc.subjectCardiovascular Diseases
dc.subjectCellular and Molecular Physiology
dc.subjectImmunotherapy
dc.titleImmunotherapy for Infarcts: In Vivo Postinfarction Macrophage Modulation Using Intramyocardial Microparticle Delivery of Map4k4 Small Interfering RNA
dc.typeJournal Article
dc.source.journaltitleBioResearch open access
dc.source.volume9
dc.source.issue1
dc.identifier.legacyfulltexthttps://escholarship.umassmed.edu/cgi/viewcontent.cgi?article=5521&amp;context=oapubs&amp;unstamped=1
dc.identifier.legacycoverpagehttps://escholarship.umassmed.edu/oapubs/4491
dc.identifier.contextkey21479073
refterms.dateFOA2022-08-23T16:50:40Z
html.description.abstract<p>The myeloid cells infiltrating the heart early after acute myocardial infarction elaborate a secretome that largely orchestrates subsequent ventricular wall repair. Regulating this innate immune response could be a means to improve infarct healing. To pilot this concept, we utilized (beta1,3-d-) glucan-encapsulated small interfering RNA (siRNA)-containing particles (GeRPs), targeting mononuclear phagocytes, delivered to mice as a one-time intramyocardial injection immediately after acute infarction. Findings demonstrated that cardiac macrophages phagocytosed GeRPs in vivo and had little systemic dissemination, thus providing a means to deliver local therapeutics. Acute infarcts were then injected in vivo with phosphate-buffered saline (PBS; vehicle) or GeRPs loaded with siRNA to Map4k4, and excised hearts were examined at 3 and 7 days by quantitative polymerase chain reaction, flow cytometry, and histology. Compared with infarcted PBS-treated hearts, hearts with intrainfarct injections of siRNA-loaded GeRPs exhibited 69-89% reductions in transcripts for Map4k4 (mitogen-activated protein kinase kinase kinase kinase 4), interleukin (IL)-1beta, and tumor necrosis factor alpha at 3 days. Expression of other factors relevant to matrix remodeling-monocyte chemoattractant protein-1 (MCP-1), matrix metalloproteinases, hyaluronan synthases, matricellular proteins, and profibrotic factors transforming growth factor beta (TGF-beta), and connective tissue growth factor (CTGF)-were also decreased. Most effects peaked at 3 days, but, in some instances (Map4k4, IL-1beta, TGF-beta, CTGF, versican, and periostin), suppression persisted to 7 days. Thus, direct intramyocardial GeRP injection could serve as a novel and clinically translatable platform for in vivo RNA delivery to intracardiac macrophages for local and selective immunomodulation of the infarct microenvironment.</p>
dc.identifier.submissionpathoapubs/4491
dc.contributor.departmentProgram in Molecular Medicine
dc.contributor.departmentDivision of Cardiovascular Medicine, Department of Medicine
dc.source.pages258-268


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Copyright Jun Luo et al., 2020; Published by Mary Ann Liebert, Inc. This Open Access article is distributed under the terms of the Creative Commons License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Except where otherwise noted, this item's license is described as Copyright Jun Luo et al., 2020; Published by Mary Ann Liebert, Inc. This Open Access article is distributed under the terms of the Creative Commons License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.