Abstract 15147: Targeted Activation of Peroxisome Proliferator-Activated Receptor Gamma (PPARG) Rapidly Suppresses Inflammation Through Inhibition of Toll-Like Receptor 4/Nuclear Factor-kappa B (TLR4/NF-kappa B) Pathway and Further Shifts Advanced Atheroma Into a Stable Phenotype

• Published in: Circulation (New York, N.Y.) Vol. 140; no. Suppl_1 Suppl 1; p. A15147
• Main Authors: Song, Joon Woo, Nam, Hyeong Soo, Park, Hyun-Sang, Kim, Sunwon, Kim, Hyun Jung, Kim, Yeon Hoon, Ahn, Jae Won, Choi, Jah Yeon, Kang, Dong Oh, Lee, Seung-Yul, Oh, Wang-Yuhl, Yoo, Hongki, Park, Kyeongsoon, Kim, Jin Won
• Format: Journal Article
• Language: English
• Published: by the American College of Cardiology Foundation and the American Heart Association, Inc 19.11.2019
• ISSN: 0009-7322; 1524-4539
• DOI: 10.1161/circ.140.suppl_1.15147

IntroductionMacrophages are major contributors of atherosclerotic plaque progression and destabilization. In our previous study, macrophage mannose receptor (MMR)-targeted delivery of PPARγ agonist for 4 weeks could effectively reduce plaque burden and inflammation in murine atheroma.HypothesisWe hypothesize that MMR-targeted theranostic agent loaded with a PPARγ agonist could 1) rapidly reduce the plaque inflammation in advanced atheroma through inhibition of TLR4/NF-κB signalling pathway and 2) subsequently modulate these inflamed plaques into a stable phenotype.Method and ResultsMMR-targeted theranostic agent was constructed by loading lobeglitazone (Lobe), a PPARγ agonist, into the MMR-targeted carrier conjugated with cyanine (Cy) dye (MMR-Lobe-Cy). We investigated its acute anti-inflammatory effects and mechanism both in in vitro and in vivo experiments, and further evaluated the prolonged effects of acute anti-inflammation on plaque composition. In vivo Day 0 and 7 serial optical coherence tomography (OCT) - near infrared fluorescence (NIRF) imaging was performed in atheromatous rabbit aorta. MMR-Lobe-Cy markedly reduced plaque inflammation without undesirable side effects (Figure A). Western blotting and immunohistochemical analysis demonstrated that anti-inflammatory effect of MMR-Lobe-Cy was mediated by inhibiting the TLR4/NF-κB signalling pathway. Furthermore, acute resolution of inflammation altered the plaque into a stable phenotype with collagen-rich matrix, decreased matrix metalloproteinase 9 (MMP-9) activity and reduced plaque macrophages on Day 14 (Figure B).ConclusionMMR-Lobe-Cy showed a robust acute anti-inflammatory effect on inflamed plaque in coronary-sized arteries by inhibition of TLR4/NF-κB pathway, and shifted the plaque compositions into a stable phenotype. This novel theranostics could be a promising therapeutic strategy to prevent the acute complications of advanced atherosclerosis.