Luan Fei, Rao Zhili, Peng Lixia, Lei Ziqin, Zeng Jiuseng, Peng Xi, Yang Ruocong, Liu Rong, Zeng Nan
State Key Laboratory of Southwestern Chinese Medicine Resources, 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.
Phytomedicine. 2022 Jun;100:154047. doi: 10.1016/j.phymed.2022.154047. Epub 2022 Mar 13.
Cinnamic acid (CA) is an active organic acid compound extracted from Cinnamomi ramulus that has various biological activities. There is growing studies have shown that the nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome significantly contributes to sterile inflammatory response and pyroptosis in myocardial ischemia/reperfusion injury (MI/RI). However, whether CA has any influence on NLRP3 inflammasome and pyroptosis during MI/RI are not fully elucidated.
In the present study, we investigated whether NLRP3 inflammasome activation and pyroptosis were involved in the cardioprotective effect of CA against MI/RI.
Male Sprague-Dawley rats were intragastrically administered either with CA (75 and 150 mg/kg, daily) or vehicle for 7 successive days prior to ligation of coronary artery, and then rats were subjected to ligation of the left anterior descending coronary artery for 30 min followed by reperfusion for 120 min to evoke MI/RI.
Our results demonstrated that CA could significantly improve cardiac diastolic function, decrease cardiac infarct size and myocardial injury enzymes, inhibit cardiomyocyte apoptosis, attenuate cardiac structure abnormality, and mitigate oxidative stress and inflammatory response. We also found that MI/RI activate NLRP3 inflammasome as evidenced by the upregulation levels of NLRP3, pro-caspase-1, caspase-1, and ASC proteins and mRNA. More importantly, MI/RI trigger pyroptosis as indicated by increased DNA fragmentation, membrane pore formation, and mitochondrial swelling as well as increased levels of pyroptosis-related proteins and mRNA, including GSDMD, N-GSDMD, IL-18, and IL-1β. As expected, all these deleterious alterations were prominently reversed by CA pretreatment.
These findings indicate that CA effectively protected cardiomyocytes against MI/RI by inhibiting NLRP3/Caspase-1/GSDMD signaling pathway, and it is worthy of more investigations for its therapeutic potential for extenuating ischemic heart disease.
肉桂酸（CA）是从桂枝中提取的一种具有多种生物活性的活性有机酸化合物。越来越多的研究表明，核苷酸结合寡聚化结构域样受体家族含pyrin结构域3（NLRP3）炎性小体在心肌缺血/再灌注损伤（MI/RI）的无菌性炎症反应和细胞焦亡中起重要作用。然而，CA在MI/RI期间对NLRP3炎性小体和细胞焦亡是否有任何影响尚未完全阐明。
在本研究中，我们探讨了NLRP3炎性小体激活和细胞焦亡是否参与了CA对MI/RI的心脏保护作用。
雄性Sprague-Dawley大鼠在冠状动脉结扎前连续7天每天灌胃给予CA（75和150mg/kg）或溶剂，然后结扎左冠状动脉前降支30分钟，再灌注120分钟以诱发MI/RI。
我们的结果表明，CA可显著改善心脏舒张功能，减小心脏梗死面积和心肌损伤酶水平，抑制心肌细胞凋亡，减轻心脏结构异常，并减轻氧化应激和炎症反应。我们还发现，MI/RI激活了NLRP3炎性小体，表现为NLRP3、前半胱天冬酶-1、半胱天冬酶-1和ASC蛋白及mRNA水平上调。更重要的是，MI/RI引发了细胞焦亡，表现为DNA片段化增加、膜孔形成和线粒体肿胀，以及细胞焦亡相关蛋白和mRNA水平增加，包括GSDMD、N-GSDMD、IL-18和IL-1β。正如预期的那样，CA预处理显著逆转了所有这些有害改变。
这些发现表明，CA通过抑制NLRP3/半胱天冬酶-1/GSDMD信号通路有效保护心肌细胞免受MI/RI损伤，其减轻缺血性心脏病的治疗潜力值得进一步研究。
