Science and Technology Achievement Incubation Center, Kunming Medical University, Kunming, China.
Department of Anatomy, Faculty of Basic Medical Sciences, Kunming Medical University, Kunming, China.
J Cell Mol Med. 2021 Jun;25(12):5769-5781. doi: 10.1111/jcmm.16600. Epub 2021 May 10.
Abnormal accumulation of lipids and massive deposition of foam cells is a primary event in the pathogenesis of atherosclerosis. Recent studies have demonstrated that autophagy and lysosomal function of atherosclerotic macrophages are impaired, which exacerbates the accumulation of lipid in macrophages and formation of foam cells. Gastrodin, a major active component of Gastrodia elata Bl., has exerted a protective effect on nervous system, but the effect of gastrodin on atherosclerotic vascular disease remains unknown. We aimed to evaluate the effect of gastrodin on autophagy and lysosomal function of foam cells and explored the mechanism underlying gastrodin's effect on the formation of foam cells. In an in vitro foam cell model constructed by incubating macrophages with oxygenized low-density lipoproteins (ox-LDL), our results showed that lysosomal function and autophagy of foam cells were compromised. Gastrodin restored lysosomal function and autophagic activity via the induction of lysosomal biogenesis and autophagy. The restoration of lysosomal function and autophagic activity enhanced cholesterol efflux from macrophages, therefore, reducing lipid accumulation and preventing formation of foam cells. AMP-activated protein kinase (AMPK) was activated by gastrodin to promote phosphorylation and nuclear translocation of forkhead box O1 (FoxO1), subsequently resulting in increased transcription factor EB (TFEB) expression. TFEB was activated by gastrodin to promote lysosomal biogenesis and autophagy. Our study revealed that the effect of gastrodin on foam cell formation and that induction of lysosomal biogenesis and autophagy of foam cells through AMPK-FoxO1-TFEB signalling axis may be a novel therapeutic target of atherosclerosis.
脂质异常积累和泡沫细胞的大量沉积是动脉粥样硬化发病机制中的主要事件。最近的研究表明，动脉粥样硬化巨噬细胞的自噬和溶酶体功能受损，这加剧了巨噬细胞中脂质的积累和泡沫细胞的形成。天麻素是天麻的主要活性成分之一，对神经系统有保护作用，但天麻素对动脉粥样硬化性血管疾病的作用尚不清楚。我们旨在评估天麻素对泡沫细胞自噬和溶酶体功能的影响，并探讨天麻素影响泡沫细胞形成的机制。在通过用氧化型低密度脂蛋白（ox-LDL）孵育巨噬细胞构建的体外泡沫细胞模型中，我们的结果表明泡沫细胞的溶酶体功能和自噬受到损害。天麻素通过诱导溶酶体生物发生和自噬来恢复溶酶体功能和自噬活性。溶酶体功能和自噬活性的恢复促进了巨噬细胞中的胆固醇流出，从而减少了脂质积累并防止了泡沫细胞的形成。天麻素激活 AMP 激活的蛋白激酶（AMPK），促进叉头框 O1（FoxO1）的磷酸化和核易位，进而导致转录因子 EB（TFEB）表达增加。天麻素激活 TFEB 以促进溶酶体生物发生和自噬。我们的研究表明，天麻素对泡沫细胞形成的影响以及通过 AMPK-FoxO1-TFEB 信号通路诱导泡沫细胞的溶酶体生物发生和自噬可能是动脉粥样硬化的一个新的治疗靶点。
