背景:目前在临床实践中没有针对心力衰竭的特异性治疗药物。许多研究已经验证了人参皂苷Rb1的功效,人参皂苷Rb1是一种在各种用于治疗心力衰竭的草药中发现的活性成分,有效改善心肌缺血。然而,人参皂苷Rb1的确切作用机制和分子靶点尚不清楚。
目的:本研究旨在探讨人参皂苷Rb1靶向DUSP-1-TMBIM-6-VDAC1轴协同调节心力衰竭患者肠道菌群和线粒体质控网络的分子机制。
方法:本研究利用DUSP-1/VDAC1基因敲除(DUSP-1-/-/VDAC1-/-)和DUSP-1/VDAC1转基因(DUSP-1+/+/VDAC1+/+)心力衰竭小鼠模型,通过横向主动脉缩窄(TAC)手术和遗传修饰技术建立。随后用人参皂苷Rb1对小鼠进行处理。
方法:进行了一系列后续的多组学分析,包括肠道菌群的评估,基因转录测序,单细胞数据库,和原代心肌细胞的分子生物学分析,探讨人参皂苷Rb1的作用机制。
结果:人参皂苷Rb1对线粒体具有多种调控机制。值得注意的是,发现DUSP-1是人参皂苷Rb1的关键分子靶标,可控制肠道菌群和线粒体功能。DUSP-1对炎症和线粒体质量控制的调节作用是由TMBIM-6和VDAC1的变化介导的。此外,发现NLRP3介导的炎症反应与线粒体质量控制相互作用,在应激条件下加剧心肌损伤。人参皂苷Rb1调制DUSP-1-TMBIM-6-VDAC1轴,抑制促炎因子的释放,改变了肠道菌群的结构组成,和保护心脏功能受损。这些作用间接影响了炎症之间的串扰,线粒体,和肠道菌群。
结论:DUSP-1-TMBIM-6-VDAC1轴,人参皂苷Rb1调控的上游通路,是人参皂苷Rb1通过调节炎症改善心力衰竭心功能的深层机制,线粒体,和肠道菌群。
BACKGROUND: There is currently no specific therapeutic drug available for heart failure in clinical practice. Numerous studies have validated the efficacy of Ginsenoside Rb1, an active component found in various herbal remedies used for heart failure treatment, in effectively ameliorating myocardial ischemia. However, the precise mechanism of action and molecular targets of Ginsenoside Rb1 remain unclear.
OBJECTIVE: This study aims to explore the molecular mechanisms through which Ginsenoside Rb1 synergistically modulates the gut flora and mitochondrial quality control network in heart failure by targeting the DUSP-1-TMBIM-6-VDAC1 axis.
METHODS: This study utilized DUSP-1/VDAC1 knockout (DUSP-1-/-/VDAC1-/-) and DUSP-1/VDAC1 transgenic (DUSP-1+/+/VDAC1+/+) mouse models of heart failure, established through Transverse Aortic Constriction (TAC) surgery and genetic modification techniques. The mice were subsequently subjected to treatment with Ginsenoside Rb1.
METHODS: A series of follow-up multi-omics analyses were conducted, including assessments of intestinal flora, gene transcription sequencing, single-cell databases, and molecular biology assays of primary cardiomyocytes, to investigate the mechanism of action of Ginsenoside Rb1.
RESULTS: Ginsenoside Rb1 was found to have multiple regulatory mechanisms on mitochondria. Notably, DUSP-1 was discovered to be a crucial molecular target of Ginsenoside Rb1, controlling both intestinal flora and mitochondrial function. The regulatory effects of DUSP-1 on inflammation and mitochondrial quality control were mediated by changes in TMBIM-6 and VDAC1. Furthermore, NLRP3-mediated inflammatory responses were found to interact with mitochondrial quality control, exacerbating myocardial injury under stress conditions. Ginsenoside Rb1 modulated the DUSP-1-TMBIM-6-VDAC1 axis, inhibited the release of pro-inflammatory factors, altered the structural composition of the gut flora, and protected impaired heart function. These effects indirectly influenced the crosstalk between inflammation, mitochondria, and gut flora.
CONCLUSIONS: The DUSP-1-TMBIM-6-VDAC1 axis, an upstream pathway regulated by Ginsenoside Rb1, is a profound mechanism through which Ginsenoside Rb1 improves cardiac function in heart failure by modulating inflammation, mitochondria, and gut flora.