期刊
CARDIOVASCULAR RESEARCH
卷 115, 期 2, 页码 419-431出版社
OXFORD UNIV PRESS
DOI: 10.1093/cvr/cvy200
关键词
Myocardial infarction; Ischaemia reperfusion; Inflammation; Macrophage
资金
- Ministry of Education, Science, and Culture, Tokyo, Japan [25461135, 23790863, 23790861]
- Ministry of Health Labor and Welfare, Tokyo, Japan (Health Science Research Grants, Research on Translational Research, Intractable Diseases, and Nanomedicine)
- Intractable Diseases Overcome Research Project from the Japan Agency for Medical Research and Development (AMED)
- JST CREST, Japan [JPMJCR17H5]
- Grants-in-Aid for Scientific Research [23790861, 25461135, 23790863] Funding Source: KAKEN
Aims Monocyte-mediated inflammation is a major mechanism underlying myocardial ischaemia-reperfusion (IR) injury and the healing process after acute myocardial infarction (AMI). However, no definitive anti-inflammatory therapies have been developed for clinical use. Pioglitazone, a peroxisome proliferator-activated receptor-gamma (PPAR) agonist, has unique anti-inflammatory effects on monocytes/macrophages. Here, we tested the hypothesis that nanoparticle (NP)-mediated targeting of pioglitazone to monocytes/macrophages ameliorates IR injury and cardiac remodelling in preclinical animal models. Methods and results We formulated poly (lactic acid/glycolic acid) NPs containing pioglitazone (pioglitazone-NPs). In a mouse IR model, these NPs were delivered predominantly to circulating monocytes and macrophages in the IR heart. Intravenous treatment with pioglitazone-NPs at the time of reperfusion attenuated IR injury. This effect was abrogated by pre-treatment with the PPAR antagonist GW9662. In contrast, treatment with a pioglitazone solution had no therapeutic effects on IR injury. Pioglitazone-NPs inhibited Ly6C(high) inflammatory monocyte recruitment as well as inflammatory gene expression in the IR hearts. In a mouse myocardial infarction model, intravenous treatment with pioglitazone-NPs for three consecutive days, starting 6h after left anterior descending artery ligation, attenuated cardiac remodelling by reducing macrophage recruitment and polarizing macrophages towards the pro-healing M2 phenotype. Furthermore, pioglitazone-NPs significantly decreased mortality after MI. Finally, in a conscious porcine model of myocardial IR, pioglitazone-NPs induced cardioprotection from reperfused infarction, thus providing pre-clinical proof of concept. Conclusion NP-mediated targeting of pioglitazone to inflammatory monocytes protected the heart from IR injury and cardiac remodelling by antagonizing monocyte/macrophage-mediated acute inflammation and promoting cardiac healing after AMI.
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