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Dihydromyricetin increases endothelial nitric oxide production and inhibits atherosclerosis through microRNA-21 in apolipoprotein E-deficient mice.

ABSTRACT: 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 from Ampelopsis 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 in Apoe- / - 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 in Apoe- / - 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.

SUBMITTER: Yang D

PROVIDER: S-EPMC7214150 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature

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Dihydromyricetin increases endothelial nitric oxide production and inhibits atherosclerosis through microRNA-21 in apolipoprotein E-deficient mice.

Yang Dafeng D Yang Zhousheng Z Chen Lei L Kuang Dabin D Zou Yang Y Li Jie J Deng Xu X Luo Songyuan S Luo Jianfang J He Jun J Yan Miao M He Guixia G Deng Yang Y Li Rong R Yuan Qiong Q Zhou Yangzhao Y Jiang Pei P Tan Shenglan S

Journal of cellular and molecular medicine 20200417 10

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 from Ampelopsis 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 ...[more]

PMID: 32301289

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Project description:OBJECTIVE:VWF (von Willebrand factor) is synthesized by endothelial cells and megakaryocytes and is known to contribute to atherosclerosis. In vitro studies suggest that platelet-derived VWF (Plt-VWF) is biochemically and functionally different from endothelial cell-derived VWF (EC-VWF). We determined the role of different pools of VWF in the pathophysiology of atherosclerosis. APPROACH AND RESULTS:Using bone marrow transplantation, we generated chimeric Plt-VWF, EC-VWF, and Plt-VWF mice lacking a disintegrin and metalloprotease with thrombospondin type I repeats-13 in platelets and plasma on apolipoprotein E-deficient (Apoe-/-) background. Controls were chimeric Apoe-/- mice transplanted with bone marrow from Apoe-/- mice (wild type) and Vwf-/-Apoe-/- mice transplanted with bone marrow from Vwf-/-Apoe-/- mice (VWF-knock out). Susceptibility to atherosclerosis was evaluated in whole aortae and cross-sections of the aortic sinus in female mice fed a high-fat Western diet for 14 weeks. VWF-knock out, Plt-VWF, and Plt-VWF mice lacking a disintegrin and metalloprotease with thrombospondin type I repeats-13 exhibited reduced plaque size characterized by smaller necrotic cores, reduced neutrophil and monocytes/macrophages content, decreased MMP9 (matrix metalloproteinase), MMP2, and CX3CL1 (chemokine [C-X3-C motif] ligand 1)-positive area, and abundant interstitial collagen (P<0.05 versus wild-type or EC-VWF mice). Atherosclerotic lesion size and composition were comparable between wild-type or EC-VWF mice. Together these findings suggest that EC-VWF, but not Plt-VWF, promotes atherosclerosis exacerbation. Furthermore, intravital microscopy experiments revealed that EC-VWF, but not Plt-VWF, contributes to platelet and leukocyte adhesion under inflammatory conditions at the arterial shear rate. CONCLUSIONS:EC-VWF, but not Plt-VWF, contributes to VWF-dependent atherosclerosis by promoting platelet adhesion and vascular inflammation. Plt-VWF even in the absence of a disintegrin and metalloprotease with thrombospondin type I repeats-13, both in platelet and plasma, was not sufficient to promote atherosclerosis.

Dataset Information

Dihydromyricetin increases endothelial nitric oxide production and inhibits atherosclerosis through microRNA-21 in apolipoprotein E-deficient mice.

Publications

Dihydromyricetin increases endothelial nitric oxide production and inhibits atherosclerosis through microRNA-21 in apolipoprotein E-deficient mice.

Similar Datasets

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