Beijing Key Laboratory of Drug Targets Identification and Drug Screening, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100050, China.
Beijing Key Laboratory of Polymorphic Drug, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100050, China.
Biochem Biophys Res Commun. 2020 May 7;525(3):759-766. doi: 10.1016/j.bbrc.2020.02.147. Epub 2020 Mar 4.
Formononetin (FN), a methoxy isoflavone abundant in many plants and herbs, has been evidently proven to possess multiple medicinal properties. Our study aimed to clarify the impact of FN on myocardial ischemia/reperfusion (I/R) injury (MIRI) and the involved mechanism. A rat model of MIRI was produced by ligation and loosening of the left anterior descending (LAD) branch of the coronary artery. Rats received 10 and 30 mg/kg of FN when the reperfusion started. At 24 h after surgery, cardiac function, infarct size, and sera levels of the cardiac markers and inflammatory mediators were measured. To mimic the inflammasome activation in cardiomyocytes, neonatal rat cardiomyocytes (NRCMs) were cultured and treated with lipopolysaccharide (LPS) plus nigericin. Cell death and reactive oxygen species (ROS) were determined. Myocardial expression and activation of the nucleotide-binding domain and leucine-rich repeat-containing protein 3 (NLRP3) inflammasome in rats were examined by western blotting. The level of thioredoxin interacting protein (TXNIP)-NLRP3 interaction was assessed. FN notably attenuated cardiac dysfunction, infarct size, release of cardiac markers, and elevation of TNF-α, IL-1β, and IL-6. FN alleviated LPS plus nigericin-induced injury and ROS increase in NRCMs. Western blotting revealed that FN suppressed the activation of NLRP3 inflammasome and TXNIP-NLRP3 interaction in rats. These findings indicate that FN ameliorated MIRI in rats and inhibited the activation of the NLRP3 inflammasome, at least partially, attributable to suppression of the ROS-TXNIP-NLRP3 pathway.
芒柄花素（FN）是一种在许多植物和草药中含量丰富的甲氧基异黄酮，已被证实具有多种药用特性。我们的研究旨在阐明 FN 对心肌缺血/再灌注（I/R）损伤（MIRI）的影响及其作用机制。通过结扎和松开冠状动脉左前降支（LAD）分支，建立大鼠 MIRI 模型。在再灌注开始时，大鼠给予 10 和 30 mg/kg FN。手术后 24 小时，测量心脏功能、梗死面积以及血清中心脏标志物和炎症介质水平。为了模拟心肌细胞中炎症小体的激活，培养新生大鼠心肌细胞（NRCMs）并用脂多糖（LPS）加 Nigericin 处理。测定细胞死亡和活性氧（ROS）。通过 Western blot 检测大鼠心肌中核苷酸结合域和富含亮氨酸重复序列蛋白 3（NLRP3）炎症小体的表达和激活。评估硫氧还蛋白相互作用蛋白（TXNIP）-NLRP3 相互作用的水平。FN 显著减轻了心脏功能障碍、梗死面积、心脏标志物的释放以及 TNF-α、IL-1β 和 IL-6 的升高。FN 减轻了 LPS 加 Nigericin 诱导的 NRCMs 损伤和 ROS 增加。Western blot 显示 FN 抑制了大鼠 NLRP3 炎症小体的激活和 TXNIP-NLRP3 相互作用。这些发现表明 FN 改善了大鼠的 MIRI，并抑制了 NLRP3 炎症小体的激活，至少部分归因于抑制 ROS-TXNIP-NLRP3 途径。
