Kanglexin, a novel anthraquinone compound, protects against myocardial ischemic injury in mice by suppressing NLRP3 and pyroptosis
Kanglexin, a novel anthraquinone compound, protects against myocardial ischemic injury in mice by suppressing NLRP3 and pyroptosis
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康乐欣是一种新型蒽醌化合物，通过抑制 NLRP3 和细胞焦亡来预防小鼠心肌缺血性损伤。
DOI：
10.1038/s41401-019-0307-8
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发表时间：
2020-03-01
影响因子：
8.2
通讯作者：
Yang, Bao-feng
中科院分区：
文献类型：
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作者：
Bian, Yu;Li, Xin;Yang, Bao-feng
细胞焦亡是炎症细胞死亡的一种形式，可能是由心肌梗塞 (MI) 后核苷酸结合寡聚化结构域样受体家族含热蛋白结构域 3 (NLRP3) 炎症小体激活驱动的。新的证据表明，通过靶向 NLRP3 和焦亡来改善 MI 引起的心肌损伤具有治疗潜力。在本研究中，我们研究了一种新型蒽醌化合物（4,5-二羟基-7-甲基-9,10-蒽醌-2-乙基琥珀酸酯）康乐欣（KLX）的体内和体外心肌保护作用。雄性 C57BL/6 小鼠在结扎冠状动脉之前连续 7 天用 KLX（20、40mg·kg−1/天，灌胃）或载体进行预处理，以诱导永久性 MI。 MI 后 24 小时，与媒介物治疗的小鼠相比，KLX 给药剂量依赖性地减少了心肌梗塞面积和乳酸脱氢酶释放，并改善了心脏功能。我们发现，MI 触发 NLRP3 炎症小体激活，导致白细胞介素 1β (IL-1β) 和 IL-18 在心脏中转化为活性成熟形式，从而扩大梗塞范围并导致心脏功能障碍。我们还表明，MI 会诱导焦亡，表现为 DNA 碎片增加、线粒体肿胀和细胞膜破裂，以及焦亡相关蛋白水平增加，包括gasdermin D、N 端 GSDMD 和 cleaved caspase-1。 KLX 阻止了所有这些有害的改变。在缺氧或脂多糖 (LPS) 处理的新生小鼠心室心肌细胞中，我们发现 KLX (10μM) 降低了末端脱氧核苷酸转移酶 dUTP 缺口末端标记阳性细胞和碘化丙啶阳性细胞以及细胞焦亡相关蛋白的升高水平。我们的结论是，KLX 至少部分通过减弱 NLRP3 和随后的心肌细胞焦亡来预防 MI 引起的心脏损伤和心脏功能障碍，并且值得对其缓解缺血性心脏病的潜力进行更严格的研究。
Pyroptosis is a form of inflammatory cell death that could be driven by the nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome activation following myocardial infarction (MI). Emerging evidence suggests the therapeutic potential for ameliorating MI-induced myocardial damages by targeting NLRP3 and pyroptosis. In this study, we investigated the myocardial protection effect of a novel anthraquinone compound (4,5-dihydroxy-7-methyl-9,10-anthraquinone-2-ethyl succinate) named Kanglexin (KLX) in vivo and in vitro. Male C57BL/6 mice were pre-treated either with KLX (20, 40 mg· kg−1per day, intragastric gavage) or vehicle for 7 consecutive days prior to ligation of coronary artery to induce permanent MI. KLX administration dose-dependently reduced myocardial infarct size and lactate dehydrogenase release and improved cardiac function as compared to vehicle-treated mice 24 h after MI. We found that MI triggered NLRP3 inflammasome activation leading to conversion of interleukin-1β (IL-1β) and IL-18 into their active mature forms in the heart, which could expand the infarct size and drive cardiac dysfunction. We also showed that MI induced pyroptosis, as evidenced by increased DNA fragmentation, mitochondrial swelling, and cell membrane rupture, as well as increased levels of pyroptosis-related proteins, including gasdermin D, N-terminal GSDMD, and cleaved caspase-1. All these detrimental alterations were prevented by KLX. In hypoxia- or lipopolysaccharide (LPS)-treated neonatal mouse ventricular cardiomyocytes, we showed that KLX (10 μM) decreased the elevated levels of terminal deoxynucleotidyl transferase dUTP nick end labeling- and propidium iodide-positive cells, and pyroptosis-related proteins. We conclude that KLX prevents MI-induced cardiac damages and cardiac dysfunction at least partly through attenuating NLRP3 and subsequent cardiomyocyte pyroptosis, and it is worthy of more rigorous investigations for its potential for alleviating ischemic heart disease.