Nanoparticle incorporating Toll-like receptor 4 inhibitor attenuates myocardial ischaemia–reperfusion injury by inhibiting monocyte-mediated inflammation in mice. Issue 7 (9th March 2019)

• Record Type: Journal Article
• Authors: Fujiwara, Masaki; Matoba, Tetsuya; Koga, Jun-Ichiro; Okahara, Arihide; Funamoto, Daiki; Nakano, Kaku; Tsutsui, Hiroyuki; Egashira, Kensuke
• Is Part Of: Cardiovascular research. Volume 115:Issue 7(2019)
• Page Start: 1244
• Page End: 1255
• Publication Date: 2019-03-09
• Subjects: Innate immunity -- TLR4 -- Ischaemia–reperfusion -- Monocyte -- Nanoparticle; Cardiovascular system -- Diseases -- Periodicals; Cardiovascular system -- Periodicals; 616.1
• DOI: 10.1093/cvr/cvz066
• Languages: English
• ISSNs: 0008-6363

Abstract

Abstract: Aims: Myocardial ischaemia–reperfusion (IR) injury hampers the therapeutic effect of revascularization in patients with acute myocardial infarction (AMI). Innate immunity for damage-associated protein patterns promotes the process of IR injury; however, the blockade of Toll-like receptor 4 (TLR4) in myocardial IR injury has not been translated into clinical practice. Therefore, we aimed to examine whether the nanoparticle-mediated administration of TAK-242, a chemical inhibitor of TLR4, attenuates myocardial IR injury in a clinically feasible protocol in a mouse model. Methods and results: We have prepared poly-(lactic-co-glycolic acid) nanoparticles containing TAK-242 (TAK-242-NP). TAK-242-NP significantly enhanced the drug delivery to monocytes/macrophages in the spleen, blood, and the heart in mice. Intravenous administration of TAK-242-NP (containing 1.0 or 3.0 mg/kg TAK-242) at the time of reperfusion decreased the infarct size, but the TAK-242 solution did not even when administered at a dosage of 10.0 mg/kg. TAK-242-NP inhibited the recruitment of Ly-6C high monocytes to the heart, which was accompanied by decreased circulating HMGB1, and NF-κB activation and cytokine expressions in the heart. TAK-242-NP did not decrease the infarct size further in TLR4-deficient mice, confirming the TLR4-specific mechanism in the effects of TAK-242-NP. Furthermore, TAK-242-NP did not decrease the infarct size further in CCR2-deficient mice, suggesting that monocyte/macrophage-mediated inflammation is the primary therapeutic target of TAK-242-NP. Conclusion: The nanoparticle-mediated delivery of TAK-242-NP represent a novel and clinical feasible strategy in patients undergone coronary revascularization for AMI by regulating TLR4-dependent monocytes/macrophages-mediated inflammation.