BCAA exaggerated acute and chronic ischemic heart disease through promotion of NLRP3 via Sirt1.

IF 5.3 2区医学 Q1 PHARMACOLOGY & PHARMACY

Biochemical pharmacology Pub Date : 2025-07-12 DOI:10.1016/j.bcp.2025.117150

Yajie Peng, Yusen Duan, Diya Wang, Jingjing Liu, Guangyuan Zhao, Zhangyue Ji, Ji Zhang, Bo Wei

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引用次数: 0

Abstract

The study investigated the role and mechanism of branched chain amino acid (BCAA) metabolism in acute myocardial injury and ventricular remodeling post-myocardial infarction. This research employed an integrated approach, combining molecular biology with metabolomics, to investigate the influence of BCAA on acute and chronic myocardial injury both in vivo and in vitro, respectively. In acute myocardial injury, BCAA significantly aggravated acute myocardial injury as demonstrated by remarkably worsen cardiac function and exacerbated biochemical abnormalities, and increased infarct size. Furthermore, BCAA supplementation aggravated the defective metabolism of BCAA by inhibiting the activities of BCAT2, BCKDH and PP2Cm. Interestingly, BCAA dose-dependently promoted pyroptosis in cardiomyocytes via NLRP3/ASC/Caspase-1 activation and cleaved GSDMD in acute myocardial injury. On the other hand, in long-term myocardial infarction (L-MI) induced remodeling, BCAA aggravated the ventricular remodeling in L-MI, and exacerbated the impairment in BCAA metabolism by inhibiting the activities of BCAT2, BCKDH, and PP2Cm. Interestingly, BCAA promoted inflammation in cardiac fibroblasts (CF) in dose-dependently. This process was mediated by inhibiting Sirt1 and enhancing NLRP3 acetylation, thereby activating the NLRP3 inflammasome and promoting CF migration, but without the trigger of pyroptosis. While Knockdown of Sirt1 markedly inhibited NLRP3 activation induced by BCAA in CF. In summary, this study provided a theoretical foundation for developing novel strategies to prevent and treat cardiovascular diseases, and offered valuable guidance for the dietary management of patients with myocardial injury.

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BCAA通过Sirt1促进NLRP3，从而加重急性和慢性缺血性心脏病。

本研究探讨了支链氨基酸（BCAA）代谢在急性心肌损伤及心肌梗死后心室重构中的作用及机制。本研究采用分子生物学和代谢组学相结合的综合方法，分别在体内和体外研究了BCAA对急性和慢性心肌损伤的影响。在急性心肌损伤中，BCAA显著加重急性心肌损伤，表现为心功能明显恶化，生化异常加重，梗死面积增大。此外，补充BCAA通过抑制BCAT2、BCKDH和PP2Cm的活性加重了BCAA的代谢缺陷。有趣的是，在急性心肌损伤中，BCAA通过NLRP3/ASC/Caspase-1激活和裂解GSDMD，剂量依赖性地促进心肌细胞焦亡。另一方面，在长期心肌梗死（L-MI）诱导的重构中，BCAA通过抑制BCAT2、BCKDH和PP2Cm的活性，加重了L-MI心室重构，加重了BCAA代谢的损害。有趣的是，BCAA促进心脏成纤维细胞（CF）炎症呈剂量依赖性。该过程通过抑制Sirt1和增强NLRP3乙酰化介导，从而激活NLRP3炎性体，促进CF迁移，但不触发焦亡。而Sirt1敲低可显著抑制CF中BCAA诱导的NLRP3激活。综上所述，本研究为制定新的心血管疾病预防和治疗策略提供了理论基础，并为心肌损伤患者的饮食管理提供了有价值的指导。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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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.