Chemical and Biological Engineering, Seoul National University, Seoul 08826, South Korea.
Department of Medical Life Science, College of Medicine, The Catholic University of Korea, Seoul 06591, South Korea; Division of Cardiology, Department of Internal Medicine, The Catholic University of Korea, Seoul 06591, South Korea.
Acta Biomater. 2021 Nov;135:520-533. doi: 10.1016/j.actbio.2021.08.028. Epub 2021 Aug 26.
Myocardial ischemia-reperfusion (IR) generates stress-induced senescent cells (SISCs) that play an important role in the pathophysiology of adverse cardiac remodeling and heart failure via secretion of pro-inflammatory molecules and matrix-degrading proteases. Thus, removal of senescent cells using a senolytic drug could be a potentially effective treatment. However, clinical studies on cancer treatment with a senolytic drug have revealed that systemic administration of a senolytic drug often causes systemic toxicity. Herein we show for the first time that local delivery of a senolytic drug can effectively treat myocardial IR injury. We found that biodegradable poly(lactic-co-glycolic acid) nanoparticle-based local delivery of a senolytic drug (ABT263-PLGA) successfully eliminated SISCs in the IR-injured rat hearts without systemic toxicity. Consequently, the treatment ameliorated inflammatory responses and attenuated adverse remodeling. Surprisingly, the ABT263-PLGA treatment restored the cardiac function over time, whereas the cardiac function decreased over time in the no treatment group. Mechanistically, the ABT263-PLGA treatment not only markedly reduced the expression of pro-inflammatory molecules and matrix-degrading proteases, but also induced macrophage polarization from the inflammatory phase to the reparative phase via efferocytosis of apoptotic SISCs by macrophages. Therefore, the senolytic strategy with ABT263-PLGA in the early stage of myocardial IR injury may be an effective therapeutic option for myocardial infarction. STATEMENT OF SIGNIFICANCE: This study describes a local injection of senolytic drug-loaded nanoparticles that selectively kills stress-induced senescent cells (SISCs) in infarcted heart. Removal of SISCs decreases inflammatory cytokines and normal cell death. We firstly revealed that further efferocytosis of apoptotic senescent cells by macrophages restores cardiac function after myocardial ischemia-reperfusion injury. Importantly, a local injection of senolytic drug did not exhibit systemic toxicity, but a systemic injection did. Our findings not only spotlight the basic understanding of therapeutic potential of senolysis in infarcted myocardium, but also pave the way for the further application of senolytic drug for non-aging related diseases.
心肌缺血再灌注（IR）产生应激诱导的衰老细胞（SISCs），通过分泌促炎分子和基质降解蛋白酶，在心脏不良重构和心力衰竭的病理生理学中发挥重要作用。因此，使用衰老细胞清除药物（Senolytic）去除衰老细胞可能是一种潜在有效的治疗方法。然而，癌症治疗的临床研究表明，衰老细胞清除药物的全身给药常常导致全身毒性。在此，我们首次表明，衰老细胞清除药物的局部给药可以有效地治疗心肌 IR 损伤。我们发现，基于可生物降解的聚（乳酸-共-乙醇酸）纳米颗粒的衰老细胞清除药物（ABT263-PLGA）的局部递送成功地消除了 IR 损伤大鼠心脏中的 SISCs，而没有全身毒性。因此，该治疗方法改善了炎症反应并减弱了不良重构。令人惊讶的是，ABT263-PLGA 治疗随着时间的推移恢复了心脏功能，而在未治疗组中，心脏功能随着时间的推移而下降。机制上，ABT263-PLGA 治疗不仅显著降低了促炎分子和基质降解蛋白酶的表达，而且通过巨噬细胞吞噬凋亡的 SISCs，使巨噬细胞从炎症期向修复期极化。因此，心肌 IR 损伤早期的衰老细胞清除策略联合 ABT263-PLGA 可能是心肌梗死的有效治疗选择。
