China Academy of Chinese Medical Sciences, Xiyuan Hospital, Beijing 100091, China; National Clinical Research Center for Chinese Medicine Cardiology, Beijing 100091, China.
State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China.
Phytomedicine. 2022 Aug;103:154220. doi: 10.1016/j.phymed.2022.154220. Epub 2022 Jun 1.
Atherosclerosis (AS) is a key pathological factor in cardiovascular disease (CVD) and is characterized by high mortality and morbidity worldwide. Metabolic disorders, including pathoglycemia and dyslipidemia that lead to chronic inflammation, represent the prominent pathological characteristics of atherosclerotic CVD, Qing-Xin-Jie-Yu Granule (QXJYG) is a Chinese traditional decoction that has been clinically proven to be effective for patients with CVD. However, the underlying mechanisms have not been completely elucidated.
To investigate the protective effects of QXJYG against AS and its potential mechanisms.
QXJYG was orally administered at doses of 1.664 and 4.992 g·kg·d in a high-fat diet (HFD)-induced AS model using ApoE-/- mice. Histopathological and immunohistochemical analyses, ELISA, untargeted and targeted metabolomics analysis, 16S rRNA analysis, and RT-qPCR were performed to identify the therapeutic effects and mechanisms of QXJYG in treating HFD-induced AS.
QXJYG retarded HFD-induced weight gain and reduced the increased serum levels of total cholesterol, triglycerides, and low-density lipoprotein-cholesterol, whereas high-dose QXJYG increased the serum level of high-density lipoprotein-cholesterol in HFD-fed ApoE-/- mice. Meanwhile, QXJYG reduced the serum levels, as well as aortas mRNA levels of the inflammatory cytokines, IL-1β and IL-6, which indicates that QXJYG is effective against metaflammation. Mechanistically, QXJYG reshaped the gut microbiota and its associated bile acids (BAs) metabolomic phenotype, partly by increasing the levels of BA synthesis enzymes, hepatic CYP7A1, and CYP27A1, while decreasing ileal FGF15 and β-Klotho mRNA expression, favoring facilitated de novo BAs synthesis and thereby driving cholesterol catabolic excretion.
Our findings indicate that QXJYG is effective against HFD-triggered chronic inflammation, and contributes to the alleviation of AS development, and the antiatherogenic properties of QXJYG may be partly due to the remodeling of the gut microbiota and BA metabolism. Although the results are encouraging, further clinical studies of anti-AS herbal medicines are required to elucidate the full potential of the gut microbiota and BA metabolism.
动脉粥样硬化（AS）是心血管疾病（CVD）的关键病理因素，其特点是全球范围内的高死亡率和发病率。代谢紊乱，包括导致慢性炎症的血糖异常和血脂异常，是动脉粥样硬化性 CVD 的突出病理特征。清心解毒颗粒（QXJYG）是一种中药方剂，已被临床证明对 CVD 患者有效。然而，其潜在机制尚未完全阐明。
探讨 QXJYG 对 AS 的保护作用及其潜在机制。
采用载脂蛋白 E 基因敲除（ApoE-/-）小鼠的高脂饮食（HFD）诱导 AS 模型，分别给予 QXJYG 1.664 和 4.992 g·kg·d 剂量的口服治疗。通过组织病理学和免疫组织化学分析、ELISA、非靶向和靶向代谢组学分析、16S rRNA 分析和 RT-qPCR 来鉴定 QXJYG 治疗 HFD 诱导的 AS 的治疗效果和机制。
QXJYG 延缓了 HFD 诱导的体重增加，并降低了血清总胆固醇、甘油三酯和低密度脂蛋白胆固醇的升高水平，而高剂量的 QXJYG 增加了 HFD 喂养的 ApoE-/-小鼠的血清高密度脂蛋白胆固醇水平。同时，QXJYG 降低了血清和主动脉中炎症细胞因子 IL-1β 和 IL-6 的 mRNA 水平，表明 QXJYG 对代谢炎症有效。在机制上，QXJYG 重塑了肠道微生物群及其相关胆汁酸（BA）代谢组学表型，部分通过增加 BA 合成酶、肝 CYP7A1 和 CYP27A1 的水平，同时降低回肠 FGF15 和 β-Klotho mRNA 表达，有利于促进新的 BA 合成，从而促进胆固醇的代谢排泄。
我们的研究结果表明，QXJYG 对 HFD 触发的慢性炎症有效，并有助于缓解 AS 的发展，QXJYG 的抗动脉粥样硬化特性可能部分归因于肠道微生物群和 BA 代谢的重塑。尽管结果令人鼓舞，但仍需要进一步的临床研究来阐明草药抗 AS 的全部潜力。
