Phytomedicine ( IF 6.7 ) Pub Date : 2023-11-19 , DOI: 10.1016/j.phymed.2023.155227 Sheng-Quan Wang 1 , Jun Xiang 1 , Guang-Qiong Zhang 1 , Ling-Yun Fu 1 , Yi-Ni Xu 1 , Yan Chen 1 , Ling Tao 2 , Xiao-Xia Hu 3 , Xiang-Chun Shen 3
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Background
Atherosclerosis (AS) is a progressive chronic disease. Currently, cardiovascular diseases (CVDs) caused by AS is responsible for the global increased mortality. Yanshanjiang as miao herb in Guizhou of China is the dried and ripe fruit of Fructus Alpinia zerumbet. Accumulated evidences have confirmed that Yanshanjiang could ameliorate CVDs, including AS. Nevertheless, its effect and mechanism on AS are still largely unknown.
Purpose
To investigate the role of essential oil from Fructus Alpinia zerumbet (EOFAZ) on AS, and the potential mechanism.
Methods
A high-fat diet (HFD) ApoE−/− mice model of AS and a oxLDL-induced model of macrophage-derived foam cells (MFCs) were reproduced to investigate the pharmacological properties of EOFAZ on AS in vivo and foam cell formation in vitro, respectively. The underlying mechanisms of EOFAZ were investigated using Network pharmacology and molecular docking. EOFAZ effect on PPARγ protein stability was measured using a cellular thermal shift assay (CETSA). Pharmacological agonists and inhibitors and gene interventions were employed for clarifying EOFAZ's potential mechanism.
Results
EOFAZ attenuated AS progression in HFD ApoE−/− mice. This attenuation was manifested by the reduced aortic intima plaque development, increased collagen content in aortic plaques, notable improvement in lipid profiles, and decreased levels of inflammatory factors. Moreover, EOFAZ inhibited the formation of MFCs by enhancing cholesterol efflux through activiting the PPARγ-LXRα-ABCA1/G1 pathway. Interestingly, the pharmacological knockdown of PPARγ impaired the beneficial effects of EOFAZ on MFCs. Additionally, our results indicated that EOFAZ reduced the ubiquitination degradation of PPARγ, and the chemical composition of EOFAZ directly bound to the PPARγ protein, thereby increasing its stability. Finally, PPARγ knockdown mitigated the protective effects of EOFAZ on AS in HFD ApoE−/− mice.
Conclusion
These findings represent the first confirmation of EOFAZ's in vivo anti-atherosclerotic effects in ApoE−/− mice. Mechanistically, its chemical constituents can directly bind to PPARγ protein, enhancing its stability, while reducing PPARγ ubiquitination degradation, thereby inhibiting foam cell formation via activation of the PPARγ-LXRα-ABCA1/G1 pathway. Simultaneously, EOFAZ could ameliorates blood lipid metabolism and inflammatory microenvironment, thus synergistically exerting its anti-atherosclerotic effects.
中文翻译：
高良姜精油通过激活PPARγ-LXRα-ABCA1/G1信号通路改善动脉粥样硬化
背景
动脉粥样硬化（AS）是一种进行性慢性疾病。目前，由 AS 引起的心血管疾病 (CVD) 是导致全球死亡率增加的原因。燕山姜为我国贵州苗药，为高良姜的干燥成熟果实。积累的证据证实燕山江可以改善心血管疾病，包括强直性脊柱炎。然而，其对 AS 的作用和机制仍然很大程度上未知。
目的
探讨高良姜精油（EOFAZ）对AS的作用及其潜在机制。
方法
复制高脂饮食 (HFD) ApoE −/−小鼠 AS 模型和 oxLDL 诱导的巨噬细胞源性泡沫细胞 (MFC) 模型，以研究 EOFAZ 对 AS体内和体外泡沫细胞形成的药理学特性， 分别。使用网络药理学和分子对接研究了 EOFAZ 的潜在机制。使用细胞热位移测定 (CETSA) 测量 EOFAZ 对 PPARγ 蛋白稳定性的影响。采用药理学激动剂和抑制剂以及基因干预来阐明 EOFAZ 的潜在机制。
结果
EOFAZ 减弱了 HFD ApoE −/−小鼠的 AS 进展。这种减弱表现为主动脉内膜斑块发育减少、主动脉斑块中胶原蛋白含量增加、脂质谱显着改善以及炎症因子水平降低。此外，EOFAZ 通过激活 PPARγ-LXRα-ABCA1/G1 途径增强胆固醇流出，从而抑制 MFC 的形成。有趣的是，PPARγ 的药理学敲低削弱了 EOFAZ 对 MFC 的有益作用。此外，我们的结果表明，EOFAZ 减少了 PPARγ 的泛素化降解，并且 EOFAZ 的化学成分直接与 PPARγ 蛋白结合，从而提高了其稳定性。最后，PPARγ 敲低减轻了 EOFAZ 对 HFD ApoE −/−小鼠 AS 的保护作用。
结论
这些发现首次证实了 EOFAZ 在 ApoE −/−小鼠体内的抗动脉粥样硬化作用。从机理上讲，其化学成分可以直接与PPARγ蛋白结合，增强其稳定性，同时减少PPARγ泛素化降解，从而通过激活PPARγ-LXRα-ABCA1/G1途径抑制泡沫细胞形成。同时，EOFAZ可以改善血脂代谢和炎症微环境，从而协同发挥其抗动脉粥样硬化作用。
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