Peroxisome proliferator-activated receptor-gamma targeting nanomedicine promotes cardiac healing after acute myocardial infarction by skewing monocyte/macrophage polarization in preclinical animal models
Peroxisome proliferator-activated receptor-gamma targeting nanomedicine promotes cardiac healing after acute myocardial infarction by skewing monocyte/macrophage polarization in preclinical animal models
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DOI：
10.1093/cvr/cvy200
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发表时间：
2019-02-01
影响因子：
10.8
通讯作者：
Egashira, Kensuke
中科院分区：
文献类型：
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作者：
Tokutome, Masaki;Matoba, Tetsuya;Egashira, Kensuke
单核细胞介导的炎症反应是急性心肌梗死（AMI）后心肌缺血-再灌注（IR）损伤和愈合过程的主要机制。然而，尚未开发出用于临床使用的确定性抗炎疗法。吡格列酮是一种过氧化物酶体增殖物激活受体-γ（PPAR）激动剂，对单核细胞/巨噬细胞具有独特的抗炎作用。在这里，我们测试的假设，纳米粒子（NP）介导的靶向吡格列酮单核细胞/巨噬细胞改善IR损伤和心脏重塑在临床前animal models.Methods和结果我们制定了聚（乳酸/乙醇酸）纳米粒子含有吡格列酮（吡格列酮纳米粒子）。在小鼠IR模型中，这些NP主要递送至IR心脏中的循环单核细胞和巨噬细胞。在再灌注时静脉注射吡格列酮纳米粒可减轻IR损伤。这种作用被废除的预处理与过氧化物酶体增殖物激活受体拮抗剂GW 9662。相比之下，吡格列酮溶液治疗对IR损伤无治疗作用。吡格列酮-NP抑制IR心脏中Ly 6C（高）炎性单核细胞募集以及炎性基因表达。在小鼠心肌梗死模型中，从左前降支动脉结扎后6小时开始，连续三天用吡格列酮-NP静脉内治疗，通过减少巨噬细胞募集和使巨噬细胞朝向促愈合M2表型极化来减弱心脏重塑。此外，吡格列酮-NP显著降低MI后的死亡率。最后，在一个有意识的猪模型的心肌IR，吡格列酮纳米颗粒诱导再灌注梗死的心脏保护，从而提供临床前proof of concept.Conclusion NP介导的靶向吡格列酮炎症单核细胞保护心脏IR损伤和心脏重塑通过拮抗单核细胞/巨噬细胞介导的急性炎症和促进心肌梗死后心脏愈合。
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.