背景:动脉粥样硬化(AS)斑块需要致密的坏死核和坚固的纤维帽来维持稳定性。而前期研究表明,中药黄连解毒汤(HLJDD)具有稳定AS斑块的作用,潜在的机制仍然模糊。本研究旨在深入研究HLJDD通过综合研究策略改善AS的潜在机制。
方法:利用暴露于高脂饮食(HFD)的ApoE-/-小鼠的AS模型,我们用显微镜观察观察HLJDD的治疗效果,油红O染色,HE染色和Masson染色。运用网络药理学的综合技术,生物信息学,和分子对接,我们阐明了HLJDD稳定AS斑块的机制。体外实验,利用ox-LDL诱导的巨噬细胞和凋亡的血管平滑肌细胞(VSMC),评估HLJDD对细胞凋亡的影响和SLC2A1的作用。
结果:体内实验表明HLJDD在减少主动脉斑块数量方面的功效,减少脂质沉积,并增强AS小鼠的斑块稳定性。利用网络药理学和机器学习,我们将SLC2A1确定为关键的监管目标。分子对接进一步验证了HLJDD组分与SLC2A1的结合。实验证明了HLJDD对SLC2A1表达的剂量依赖性上调,放大红细胞增多症。重要的是,这种效应被SLC2A1抑制剂STF-31逆转,突出了SLC2A1作为靶标的关键作用.
结论:HLJDD可以通过增强SLC2A1的表达水平来调节巨噬细胞的吞噬,从而改善动脉粥样硬化斑块的稳定性。
BACKGROUND: Atherosclerotic (AS) plaques require a dense necrotic core and a robust fibrous cap to maintain stability. While previous studies have indicated that the traditional Chinese medicine Huang Lian Jie Du Decoction (HLJDD) possesses the capability to stabilize AS plaques, the underlying mechanisms remain obscure. This study aims to delve deeper into the potential mechanisms by which HLJDD improves AS through an integrated research strategy.
METHODS: Leveraging an AS model in ApoE-/- mice exposed to a high-fat diet (HFD), we scrutinized the therapeutic effects of HLJDD using microscopic observations, oil red O staining, HE staining and Masson staining. Employing comprehensive techniques of network pharmacology, bioinformatics, and molecular docking, we elucidated the mechanism by which HLJDD stabilizes AS plaques. In vitro experiments, utilizing ox-LDL-induced macrophages and apoptotic vascular smooth muscle cells (VSMCs), assessed the impact of HLJDD on efferocytosis and the role of SLC2A1.
RESULTS: In vivo experiments showcased the efficacy of HLJDD in reducing the quantity of aortic plaques, diminishing lipid deposition, and enhancing plaque stability in AS mice. Employing network pharmacology and machine learning, we pinpointed SLC2A1 as a crucial regulatory target. Molecular docking further validated the binding of HLJDD components with SLC2A1. The experiments demonstrated a dose-dependent upregulation in SLC2A1 expression by HLJDD, amplifying efferocytosis. Importantly, this effect was reversed by the SLC2A1 inhibitor STF-31, highlighting the pivotal role of SLC2A1 as a target.
CONCLUSIONS: The HLJDD can modulate macrophage efferocytosis by enhancing the expression levels of SLC2A1, thereby improving the stability of atherosclerotic plaques.