新型AMPK/ orp8 -脂噬轴：积雪草苷介导的抗高脂血症缺血再灌注损伤心脏保护的治疗靶点

IF 8.3 1区医学 Q1 CHEMISTRY, MEDICINAL

Phytomedicine Pub Date : 2025-09-23 DOI:10.1016/j.phymed.2025.157317

Fenlan Bian , Jun Wang , Shiyao Ni , Maonanxing Qi , Peng Zhao , Jinjun Liu , Pinfang Kang

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引用次数: 0

摘要

背景：高脂血症通过脂质代谢功能障碍和脂质毒性显著加重心肌缺血再灌注损伤。目前的证据表明，脂滴积聚和脂噬受损是高脂血症心功能障碍的关键病理机制。本研究探讨了积雪草苷（asiaticoside， AS）对高脂血症小鼠心肌I/R损伤的心脏保护作用，并阐明了其潜在机制，强调了AMPK/ orp8介导的脂质吞噬途径。方法：采用高脂饲料饲养高脂血症C57BL/6小鼠，并对其进行心肌I/R损伤。小鼠在手术前4周接受AS（12.5、25或50 mg/kg）治疗。体外实验采用棕榈酸处理H9C2心肌细胞，然后进行缺氧/再氧合。通过药理调节剂[AMPK激活剂（A-769662）和AMPK抑制剂（化合物C）]和基因操作（ORP8 siRNA敲低）来评估AMPK/ORP8信号通路的作用。结果：AS剂量依赖性改善了高脂血症I/R小鼠的心功能参数，降低了心肌梗死面积（LVEF和LVFS），降低了甘油三酯和心脏损伤生物标志物（cTnI， LDH, CK-MB）。AS治疗可显著降低心脏脂质积累和甘油三酯含量，同时提高脂肪吞噬标志物（LC3B-II和Beclin-1）并降低p62水平。在机制上，AS激活AMPK磷酸化，上调ORP8表达，并伴有脂噬通量增强。在H9C2细胞中，AS通过AMPK/ orp8依赖性的脂噬激活来保护棕榈酸诱导的脂肪毒性和H/R损伤。AMPK抑制（化合物C）或ORP8敲低显著减弱AS的保护作用，而AMPK激活（A-769,662）增强了这些益处，而ORP8沉默在一定程度上逆转了这些益处。结论：本研究表明，AS通过AMPK/ORP8信号轴促进脂肪吞噬，从而减轻高脂血症患者心肌I/R损伤。AMPK/ orp8 -脂噬通路是代谢性心血管疾病的一个新的治疗靶点，AS作为一种具有重要翻译潜力的有前途的心脏保护剂出现。

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Novel AMPK/ORP8-lipophagy axis: A therapeutic target for asiaticoside-mediated cardioprotection against ischemia-reperfusion injury in hyperlipidemia

Background

Hyperlipidemia significantly exacerbates myocardial ischemia-reperfusion (I/R) injurfy through lipid metabolic dysfunction and lipotoxicity. Current evidence suggests that lipid droplet accumulation and impaired lipophagy represent critical pathological mechanisms underlying cardiac dysfunction in hyperlipidemic conditions. This study investigated the cardioprotective effects of asiaticoside (AS) against myocardial I/R injury in hyperlipidemic mice and elucidated its underlying mechanisms, emphasizing the AMPK/ORP8-mediated lipophagy pathway.

Methods

Hyperlipidemic C57BL/6 mice were established using high-fat diet feeding and subjected to myocardial I/R injury. Mice received AS (12.5, 25, or 50 mg/kg) treatment for 4 weeks prior to surgery. In vitro experiments involved H9C2 cardiomyocytes treated with palmitic acid followed by hypoxia/reoxygenation. The role of AMPK/ORP8 signaling was evaluated using pharmacological modulators [AMPK activator (A-769662) and AMPK inhibitor (Compound C)] and genetic manipulation (ORP8 siRNA knockdown).

Results

AS dose-dependently improved cardiac function parameters, reduced myocardial infarct size (LVEF and LVFS) and decreased triglyceride and cardiac injury biomarkers (cTnI, LDH, CK-MB) in hyperlipidemic I/R mice. Treatment with AS significantly reduced cardiac lipid accumulation and triglyceride content while enhancing lipophagy markers (LC3B-II and Beclin-1) and reducing p62 levels. Mechanistically, AS activated AMPK phosphorylation and upregulated ORP8 expression, which was accompanied by enhanced lipophagy flux. In H9C2 cells, AS protected against palmitic acid-induced lipotoxicity and H/R injury through AMPK/ORP8-dependent lipophagy activation. AMPK inhibition (Compound C) or ORP8 knockdown significantly attenuated AS's protective effects, while AMPK activation (A-769,662) potentiated these benefits, which were reversed to some extent by ORP8 silencing.

Conclusions

This study demonstrates that AS mitigates myocardial I/R injury in hyperlipidemic conditions by promoting lipophagy through the AMPK/ORP8 signaling axis. The AMPK/ORP8-lipophagy pathway represents a novel therapeutic target for metabolic cardiovascular diseases, and AS emerges as a promising cardioprotective agent with significant translational potential.

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来源期刊

Phytomedicine 医学-药学

CiteScore

10.30

自引率

5.10%

发文量

670

审稿时长

91 days

期刊介绍： Phytomedicine is a therapy-oriented journal that publishes innovative studies on the efficacy, safety, quality, and mechanisms of action of specified plant extracts, phytopharmaceuticals, and their isolated constituents. This includes clinical, pharmacological, pharmacokinetic, and toxicological studies of herbal medicinal products, preparations, and purified compounds with defined and consistent quality, ensuring reproducible pharmacological activity. Founded in 1994, Phytomedicine aims to focus and stimulate research in this field and establish internationally accepted scientific standards for pharmacological studies, proof of clinical efficacy, and safety of phytomedicines.