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IF 5.3 2区医学 Q1 PHARMACOLOGY & PHARMACY Biochemical pharmacology Pub Date : 2024-09-14 DOI:10.1016/j.bcp.2024.116541

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引用次数: 0

摘要

四甲基吡嗪（TMP）属于中药川芎的有效成分，对心肌缺血再灌注（I/R）损伤有一定的保护作用。它能改善急性心肌梗死患者术后心功能，缓解心室重构。然而，其具体的保护机制仍不清楚。本研究将一定浓度的TMP引入I/R小鼠或氧糖剥夺/复氧（OGD/R）处理后的H9C2细胞，观察TMP对心肌细胞活性、细胞毒性、细胞凋亡、自噬、热解和NLRP3炎性体激活的影响。结果表明，TMP干预可减少OGD/R和I/R诱导的心肌细胞凋亡，加速细胞活性和自噬水平，并以剂量依赖的方式改善I/R小鼠的心肌组织坏死。此外，TMP通过提高I/R和OGD/R模型后心肌细胞的自噬水平，阻止了NLRP3炎性体的形成，从而抑制了热凋亡，并进一步分析了引入氯喹在体内和体外抑制自噬活性的作用，以证实TMP是否通过提高自噬水平来抑制NLRP3炎性体的激活和热凋亡、结果发现，当氯喹抑制自噬时，TMP 对 NLRP3 炎症小体的抑制作用及其对心肌损伤的保护作用被阻断。总之，本实验证明了 TMP 能异常减轻小鼠的 I/R 损伤，而这种保护作用是通过增强自噬活性来抑制 NLRP3 炎性体的活化实现的。

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Protective effects of tetramethylpyrazine on myocardial ischemia/reperfusion injury involve NLRP3 inflammasome suppression by autophagy activation

Tetramethylpyrazine (TMP) belongs to the active ingredients of the traditional Chinese medicine Chuanxiong, which has a certain protective effect in myocardial ischemia–reperfusion (I/R) injury. It can improve postoperative cardiac function and alleviate ventricular remodeling in acute myocardial infarction patients. However, its specific protective mechanism is still unclear. In this study, a certain concentration of TMP was introduced into I/R mice or H9C2 cells after oxygen-glucose deprivation/reoxygenation (OGD/R) treatment to observe the effects of TMP on cardiomyocyte activity, cytotoxicity, apoptosis, autophagy, pyroptosis, and NLRP3 inflammasome activation. The results displayed that TMP intervention could reduce OGD/R and I/R-induced cardiomyocyte apoptosis, accelerate cellular activity and autophagy levels, and ameliorate myocardial tissue necrosis in I/R mice in a dose-dependent manner. Further, TMP prevented the formation of NLRP3 inflammasomes to suppress pyroptosis by increasing the level of cardiomyocyte autophagy after I/R and OGD/R modelling, the introduction of chloroquine to suppress autophagic activity in vivo and in vitro was further analyzed to confirm whether TMP inhibits NLRP3 inflammasome activation and pyroptosis by increasing autophagy, and we found the inhibitory effect of TMP on NLRP3 inflammasomes and its protective effect against myocardial injury were blocked when autophagy was inhibited with chloroquine. In conclusion, this experiment demonstrated that TMP unusually attenuated I/R injury in mice, and this protective effect was achieved by inhibiting the activation of NLRP3 inflammasomes through enhancing autophagic activity.

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来源期刊

Biochemical pharmacology 医学-药学

CiteScore

10.30

自引率

1.70%

发文量

420

审稿时长

17 days

期刊介绍： Biochemical Pharmacology publishes original research findings, Commentaries and review articles related to the elucidation of cellular and tissue function(s) at the biochemical and molecular levels, the modification of cellular phenotype(s) by genetic, transcriptional/translational or drug/compound-induced modifications, as well as the pharmacodynamics and pharmacokinetics of xenobiotics and drugs, the latter including both small molecules and biologics. The journal''s target audience includes scientists engaged in the identification and study of the mechanisms of action of xenobiotics, biologics and drugs and in the drug discovery and development process. All areas of cellular biology and cellular, tissue/organ and whole animal pharmacology fall within the scope of the journal. Drug classes covered include anti-infectives, anti-inflammatory agents, chemotherapeutics, cardiovascular, endocrinological, immunological, metabolic, neurological and psychiatric drugs, as well as research on drug metabolism and kinetics. While medicinal chemistry is a topic of complimentary interest, manuscripts in this area must contain sufficient biological data to characterize pharmacologically the compounds reported. Submissions describing work focused predominately on chemical synthesis and molecular modeling will not be considered for review. While particular emphasis is placed on reporting the results of molecular and biochemical studies, research involving the use of tissue and animal models of human pathophysiology and toxicology is of interest to the extent that it helps define drug mechanisms of action, safety and efficacy.