PMID- 33376632
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20210430
IS  - 2164-7844 (Print)
IS  - 2164-7860 (Electronic)
IS  - 2164-7844 (Linking)
VI  - 9
IP  - 1
DP  - 2020
TI  - Immunotherapy for Infarcts: In Vivo Postinfarction Macrophage Modulation Using 
      Intramyocardial Microparticle Delivery of Map4k4 Small Interfering RNA.
PG  - 258-268
LID - 10.1089/biores.2020.0037 [doi]
AB  - 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.
CI  - (c) Jun Luo et al., 2020; Published by Mary Ann Liebert, Inc.
FAU - Luo, Jun
AU  - Luo J
AD  - Matrix Biology Program, Benaroya Research Institute at Virginia Mason, Seattle, 
      Washington, USA.
FAU - Weaver, Matthew S
AU  - Weaver MS
AD  - Matrix Biology Program, Benaroya Research Institute at Virginia Mason, Seattle, 
      Washington, USA.
FAU - Fitzgibbons, Timothy P
AU  - Fitzgibbons TP
AD  - Cardiovascular Medicine, Department of Medicine, University of Massachusetts 
      Medical School, Worcester, Massachusetts, USA.
FAU - Aouadi, Myriam
AU  - Aouadi M
AD  - Integrated Cardio Metabolic Center, Department of Medicine, Karolinska 
      Institutet, Huddinge, Sweden.
FAU - Czech, Michael P
AU  - Czech MP
AD  - Program in Molecular Medicine, University of Massachusetts Medical School, 
      Worcester, Massachusetts, USA.
FAU - Allen, Margaret D
AU  - Allen MD
AD  - Matrix Biology Program, Benaroya Research Institute at Virginia Mason, Seattle, 
      Washington, USA.
AD  - Division of Cardiothoracic Surgery, Department of Surgery, University of 
      Washington, Seattle, Washington, USA.
LA  - eng
GR  - R01 DK030898/DK/NIDDK NIH HHS/United States
GR  - R01 DK103047/DK/NIDDK NIH HHS/United States
GR  - R37 DK030898/DK/NIDDK NIH HHS/United States
PT  - Journal Article
DEP - 20201202
PL  - United States
TA  - Biores Open Access
JT  - BioResearch open access
JID - 101579333
PMC - PMC7757732
OTO - NOTNLM
OT  - Map4k4
OT  - intramyocardial
OT  - macrophage
OT  - microparticle
OT  - myocardial infarction
OT  - siRNA
COIS- None of the authors have competing financial interests.
EDAT- 2020/12/31 06:00
MHDA- 2020/12/31 06:01
PMCR- 2020/12/02
CRDT- 2020/12/30 05:21
PHST- 2020/10/21 00:00 [accepted]
PHST- 2020/12/30 05:21 [entrez]
PHST- 2020/12/31 06:00 [pubmed]
PHST- 2020/12/31 06:01 [medline]
PHST- 2020/12/02 00:00 [pmc-release]
AID - 10.1089/biores.2020.0037 [pii]
AID - 10.1089/biores.2020.0037 [doi]
PST - epublish
SO  - Biores Open Access. 2020 Dec 2;9(1):258-268. doi: 10.1089/biores.2020.0037. 
      eCollection 2020.