肉桂树枝乙酸乙酯提取物通过抑制 NLRP3 炎性小体激活和细胞焦亡对大鼠心肌缺血/再灌注损伤的心脏保护作用。
Cardioprotective activity of ethyl acetate extract of Cinnamomi Ramulus against myocardial ischemia/reperfusion injury in rats via inhibiting NLRP3 inflammasome activation and pyroptosis.
机构信息
State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan 611137, China; School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan 611137, China.
School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan 611137, China.
出版信息
Phytomedicine. 2021 Dec;93:153798. doi: 10.1016/j.phymed.2021.153798. Epub 2021 Oct 8.
BACKGROUND
NLRP3 inflammasome activation and pyroptosis play an important role in myocardial ischemia/reperfusion injury (MI/RI). Cinnamomi ramulus (CR), is an important folk medicinal plant in China, which derived from the dried twig of Cinnamomum cassia (L.) Presl, has function of "warming and tonifying heart yang", and traditionally utilized to treat the cold, blood-cold amenorrhea, phlegm, edema, arthralgia, and palpitations as well as improve blood circulation. The aqueous extract of C. ramulus was reported to show significant therapeutic potential for treating MI/RI. Whereas, there are no previous investigations in China or abroad has reported the cardioprotective effects and underlying mechanism of the ethyl acetate extract of C. ramulus (CREAE) and its bioactive substance cinnamic acid (CA) in triggering NLRP3 inflammasome activation and subsequent pyroptosis.
PURPOSE
The present study aimed to assess the cardioprotective function of CREAE and CA against the MI/RI in rats and involved the underlying mechanisms.
METHODS
The MI/RI model was established in male SD rats by occlusion of the left anterior descending coronary artery for 30 min followed by reperfusion for 120 min, respectively. The rats were intragastrically administered with CREAE (74 and 37 mg/kg) and CA (45 mg/kg) for 7 successive days before vascular ligation. The cardioprotective effects of CREAE and CA against myocardial injury of rats were detected by HE staining, TTC staining, echocardiograms, and myocardial enzymes detections. Serum levels of inflammatory factors, such as IL-6, IL-1β, and TNF-α, were analyzed by ELISA kits to evaluate the effects of CREAE and CA. The protein and gene expression levels of NLRP3 and the pyroptosis-related factors in heart tissue were conducted by western blot and RT-qPCR.
RESULTS
Our results showed that CREAE and CA decrease myocardial infarct size and improve cardiac function, mitigate myocardial damage, and repress inflammatory response in rats after I/R. Mechanistically, our results revealed that CREAE and CA can dramatically suppress the activation of NLRP3 inflammasome and subsequent cardiomyocyte pyroptosis in myocardial tissues that as evidenced by downregulating the protein and gene expressions of NLRP3, ASC, IL-1β, caspase-1, gasdermin D, and N-terminal GSDMD.
CONCLUSIONS
Our data indicated that CREAE and CA may attenuate MI/RI through suppression of NLRP3 inflammasome and subsequent pyroptosis-related signaling pathways.
背景
NLRP3 炎性小体激活和细胞焦亡在心肌缺血/再灌注损伤（MI/RI）中起着重要作用。肉桂（CR），是中国一种重要的民间药用植物，来源于肉桂（L.）Presl 的干枝。具有“温阳补心”的功效，传统上用于治疗寒、血寒闭经、痰、水肿、关节痛、心悸以及改善血液循环。据报道，肉桂的水提物对治疗 MI/RI 具有显著的治疗潜力。然而，中国或国外以前都没有报道过肉桂的乙酸乙酯提取物（CREAE）及其生物活性物质肉桂酸（CA）在触发 NLRP3 炎性小体激活和随后的细胞焦亡方面的心脏保护作用及其潜在机制。
目的
本研究旨在评估 CREAE 和 CA 对大鼠 MI/RI 的心脏保护作用及其潜在机制。
方法
通过结扎左前降支冠状动脉 30min 后再灌注 120min 分别建立雄性 SD 大鼠 MI/RI 模型。血管结扎前连续 7 天，大鼠分别灌胃给予 CREAE（74 和 37mg/kg）和 CA（45mg/kg）。通过 HE 染色、TTC 染色、超声心动图和心肌酶检测评估 CREAE 和 CA 对大鼠心肌损伤的心脏保护作用。通过 ELISA 试剂盒分析血清中炎症因子（如 IL-6、IL-1β 和 TNF-α）的水平，以评估 CREAE 和 CA 的作用。通过 Western blot 和 RT-qPCR 检测心脏组织中 NLRP3 及焦亡相关因子的蛋白和基因表达水平。
结果
结果表明，CREAE 和 CA 可减少大鼠心肌梗死面积，改善心功能，减轻心肌损伤，抑制 I/R 后大鼠的炎症反应。机制上，我们的结果表明 CREAE 和 CA 可以通过下调 NLRP3、ASC、IL-1β、caspase-1、gasdermin D 和 N 端 GSDMD 的蛋白和基因表达，显著抑制心肌组织中 NLRP3 炎性小体的激活和随后的心肌细胞焦亡。
结论
本研究数据表明，CREAE 和 CA 可能通过抑制 NLRP3 炎性小体和随后的焦亡相关信号通路来减轻 MI/RI。
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