Key result
A single intramyocardial injection of Map4k4-siRNA-loaded GeRPs reduced Map4k4 transcripts by 86% to 89% compared to vehicle, significantly dampening early inflammatory and profibrotic responses.
Why the study?
Regulating the early innate immune response of myeloid cells infiltrating the heart after acute myocardial infarction could improve infarct healing.
Does intramyocardial delivery of Map4k4 siRNA-loaded GeRPs reduce inflammatory and profibrotic gene expression in a mouse model of acute myocardial infarction?
Does intramyocardial delivery of Map4k4 siRNA-loaded GeRPs reduce inflammatory and profibrotic gene expression in a mouse model of acute myocardial infarction?
Effect estimate: 86% to 89% reduction
p-value: p=<0.001
Direct intramyocardial injection of siRNA-loaded microparticles effectively silences inflammatory genes in cardiac macrophages, offering a potential localized immunomodulatory therapy for post-infarct healing.
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 (β1,3-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)-1β, and tumor necrosis factor α 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-β), and connective tissue growth factor (CTGF)—were also decreased. Most effects peaked at 3 days, but, in some instances (Map4k4, IL-1β, TGF-β, 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.
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Luo et al. (2020) studied Acute myocardial infarction. Map4k4 siRNA-loaded GeRPs vs. Phosphate-buffered saline (PBS) was evaluated on Map4k4 gene expression (86% to 89% reduction, p=<0.001). A single intramyocardial injection of Map4k4-siRNA-loaded GeRPs reduced Map4k4 transcripts by 86% to 89% compared to vehicle, significantly dampening early inflammatory and profibrotic responses.
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