Dihydromyricetin increases endothelial nitric oxide production and inhibits atherosclerosis through microRNA-21 in apolipoprotein E-deficient mice
Dihydromyricetin increases endothelial nitric oxide production and inhibits atherosclerosis through microRNA-21 in apolipoprotein E-deficient mice
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二氢杨梅素通过载脂蛋白 E 缺陷小鼠的 microRNA-21 增加内皮一氧化氮的产生并抑制动脉粥样硬化
DOI：
10.1111/jcmm.15278
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发表时间：
2020
影响因子：
5.3
通讯作者：
Tan Shenglan
中科院分区：
文献类型：
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作者：
Yang Dafeng;Yang Zhousheng;Chen Lei;Kuang Dabin;Zou Yang;Li Jie;Deng Xu;Luo Songyuan;Luo Jianfang;He Jun;Yan Miao;He Guixia;Deng Yang;Li Rong;Yuan Qiong;Zhou Yangzhao;Jiang Pei;Tan Shenglan
从传统中草药中提取的天然产物是治疗心血管疾病的潜在药物。本研究旨在探讨从显齿蛇葡萄中提取的天然化合物二氢杨梅素（DMY）在动脉粥样硬化中的作用及其机制。DMY治疗可显著抑制动脉粥样硬化病变形成、促炎基因表达以及病变巨噬细胞和CD 4阳性T细胞流入血管壁和肝脏炎症，同时增加一氧化氮（NO）生成并改善载脂蛋白E-缺陷（Apoe−/−）小鼠的脂质代谢。然而，在接受DMY的Apoe −/−小鼠中使用NOS抑制剂L-NAME可以消除这些保护作用。从机制上讲，DMY减少microRNA-21（miR-21）并增加其靶基因二甲基精氨酸二甲氨基水解酶-1（DDAH 1）的表达，这一作用降低了不对称甲酰基精氨酸（ADMA）水平，并增加了培养的HUVEC、动脉粥样硬化病变的血管内皮和肝脏中内皮NO合酶（eNOS）磷酸化和NO产生。相比之下，Apoe −/−小鼠中miR-21的全身递送或培养的HUVECs中miR-21的过表达消除了这些DMY介导的保护作用。这些数据表明，内皮miR-21抑制DDAH 1-ADMA-eNOS-NO通路促进动脉粥样硬化的发病机制，DMY可以挽救动脉粥样硬化。因此，DMY可能代表动脉粥样硬化管理中的潜在治疗辅助剂。
Natural products were extracted from traditional Chinese herbal emerging as potential therapeutic drugs for treating cardiovascular diseases. This study examines the role and underlying mechanism of dihydromyricetin (DMY), a natural compound extracted fromAmpelopsis grossedentata, in atherosclerosis. DMY treatment significantly inhibits atherosclerotic lesion formation, proinflammatory gene expression and the influx of lesional macrophages and CD4‐positive T cells in the vessel wall and hepatic inflammation, whereas increases nitric oxide (NO) production and improves lipid metabolism in apolipoprotein E‐deficient (Apoe−/−) mice. Yet, those protective effects are abrogated by using NOS inhibitor L‐NAME inApoe−/−mice received DMY. Mechanistically, DMY decreases microRNA‐21 (miR‐21) and increases its target gene dimethylarginine dimethylaminohydrolase‐1 (DDAH1) expression, an effect that reduces asymmetric aimethlarginine (ADMA) levels, and increases endothelial NO synthase (eNOS) phosphorylation and NO production in cultured HUVECs, vascular endothelium of atherosclerotic lesions and liver. In contrast, systemic delivery of miR‐21 inApoe−/−mice or miR‐21 overexpression in cultured HUVECs abrogates those DMY‐mediated protective effects. These data demonstrate that endothelial miR‐21‐inhibited DDAH1‐ADMA‐eNOS‐NO pathway promotes the pathogenesis of atherosclerosis which can be rescued by DMY. Thus, DMY may represent a potential therapeutic adjuvant in atherosclerosis management.