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This study examines the role and underlying mechanism of dihydromyricetin (DMY), a natural compound extracted from <jats:italic>Ampelopsis grossedentata<\/jats:italic>, in atherosclerosis. DMY treatment significantly inhibits atherosclerotic lesion formation, proinflammatory gene expression and the influx of lesional macrophages and CD4\u2010positive T cells in the vessel wall and hepatic inflammation, whereas increases nitric oxide (NO) production and improves lipid metabolism in apolipoprotein E\u2010deficient (<jats:italic>Apoe<jats:sup>\u2212<\/jats:sup><\/jats:italic><jats:sup>\/<\/jats:sup><jats:italic><jats:sup>\u2212<\/jats:sup><\/jats:italic>) mice. Yet, those protective effects are abrogated by using NOS inhibitor L\u2010NAME in <jats:italic>Apoe<jats:sup>\u2212<\/jats:sup><\/jats:italic><jats:sup>\/<\/jats:sup><jats:italic><jats:sup>\u2212<\/jats:sup><\/jats:italic> mice received DMY. Mechanistically, DMY decreases microRNA\u201021 (miR\u201021) and increases its target gene dimethylarginine dimethylaminohydrolase\u20101 (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\u201021 in <jats:italic>Apoe<jats:sup>\u2212<\/jats:sup><\/jats:italic><jats:sup>\/<\/jats:sup><jats:italic><jats:sup>\u2212<\/jats:sup><\/jats:italic> mice or miR\u201021 overexpression in cultured HUVECs abrogates those DMY\u2010mediated protective effects. These data demonstrate that endothelial miR\u201021\u2010inhibited DDAH1\u2010ADMA\u2010eNOS\u2010NO pathway promotes the pathogenesis of atherosclerosis which can be rescued by DMY. Thus, DMY may represent a potential therapeutic adjuvant in atherosclerosis management.<\/jats:p>","DOI":"10.1111\/jcmm.15278","type":"journal-article","created":{"date-parts":[[2020,4,17]],"date-time":"2020-04-17T08:53:22Z","timestamp":1587113602000},"page":"5911-5925","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":53,"title":["Dihydromyricetin increases endothelial nitric oxide production and inhibits atherosclerosis through microRNA\u201021 in apolipoprotein E\u2010deficient mice"],"prefix":"10.1111","volume":"24","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8320-8215","authenticated-orcid":false,"given":"Dafeng","family":"Yang","sequence":"first","affiliation":[{"name":"Department of Pharmacy Institute of Clinical Pharmacy Second Xiangya Hospital Central South University Changsha China"},{"name":"Department of Cardiovascular Surgery Second Xiangya Hospital Central South University Changsha 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