Myocardial protection by nanomaterials formulated with CHIR99021 and FGF1
Myocardial protection by nanomaterials formulated with CHIR99021 and FGF1
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DOI：
10.1172/jci.insight.132796
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发表时间：
2020-06-18
期刊：
影响因子：
8
通讯作者：
Zhang, Jianyi
中科院分区：
文献类型：
--
作者：
Fan, Chengming;Oduk, Yasin;Zhang, Jianyi
急性心肌梗死患者的死亡率与心肌梗死面积呈线性相关。由于在哺乳动物成年心脏中，从心脏前体细胞再生心肌细胞的量很小，我们探索了一种新的治疗方法，利用纳米材料的能力随着时间的推移释放化学物质，以促进心肌保护和缩小梗塞面积。初步筛选确定了两种化合物，FGF1和CHIR99021(Wnt1激动剂/GSK-3β拮抗剂)，它们可以协同促进体外培养的心肌细胞周期。由CHIR99021和FGF1(CHIR+FGF1-NPs)组成的聚乳酸-乙醇酸纳米粒(NPs)提供了长达4周的有效缓释系统。心肌内注射CHIR+FGF1-NPs可使心肌梗死后重构的小鼠或猪模型的心肌梗死面积减少20%-30%，从而实现心肌保护。这种左心室结构的改善伴随着心脏收缩功能的保留。进一步研究发现，CHIR+FGF1NPs可减少心肌细胞凋亡，增加血管生成。因此，使用化学物质和基于NP的缓释系统协同工作的组合，这项研究展示了一种潜在的缩小急性心肌梗死心脏左室梗死面积的新疗法。
The mortality of patients suffering from acute myocardial infarction is linearly related to the infarct size. As regeneration of cardiomyocytes from cardiac progenitor cells is minimal in the mammalian adult heart, we have explored a new therapeutic approach, which leverages the capacity of nanomaterials to release chemicals over time to promote myocardial protection and infarct size reduction. Initial screening identified 2 chemicals, FGF1 and CHIR99021 (a Wnt1 agonist/GSK-3 beta antagonist), which synergistically enhance cardiomyocyte cell cycle in vitro. Poly-lactic-co-glycolic acid nanoparticles (NPs) formulated with CHIR99021 and FGF1 (CHIR + FGF1-NPs) provided an effective slow-release system for up to 4 weeks. Intramyocardial injection of CHIR + FGF1-NPs enabled myocardial protection via reducing infarct size by 20%-30% in mouse or pig models of postinfarction left ventricular (LV) remodeling. This LV structural improvement was accompanied by preservation of cardiac contractile function. Further investigation revealed that CHIR + FGF1NPs resulted in a reduction of cardiomyocyte apoptosis and increase of angiogenesis. Thus, using a combination of chemicals and an NP-based prolonged-release system that works synergistically, this study demonstrates a potentially novel therapy for LV infarct size reduction in hearts with acute myocardial infarction.