Dihydromyricetin Attenuates TNF-α-Induced Endothelial Dysfunction through miR-21-Mediated DDAH1/ADMA/NO Signal Pathway

Abstract

Accumulating studies demonstrate that dihydromyricetin (DMY), a compound extracted from Chinese traditional herb, Ampelopsis grossedentata, attenuates atherosclerotic process by improvement of endothelial dysfunction. However, the underlying mechanism remains poorly understood. Thus, the aim of this study is to investigate the potential mechanism behind the attenuating effects of DMY on tumor necrosis factor alpha- (TNF-α-) induced endothelial dysfunction. In response to TNF-α, microRNA-21 (miR-21) expression was significantly increased in human umbilical vein endothelial cells (HUVECs), in line with impaired endothelial dysfunction as evidenced by decreased tube formation and migration, endothelial nitric oxide synthase (eNOS) (ser1177) phosphorylation, dimethylarginine dimethylaminohydrolases 1 (DDAH1) expression and metabolic activity, and nitric oxide (NO) concentration as well as increased asymmetric dimethylarginine (ADMA) levels. In contrast, DMY or blockade of miR-21 expression ameliorated endothelial dysfunction in HUVECs treated with TNF-α through downregulation of miR-21 expression, whereas these effects were abolished by overexpression of miR-21. In addition, using a nonspecific NOS inhibitor, L-NAME, also abrogated the attenuating effects of DMY on endothelial dysfunction. Taken together, these data demonstrated that miR-21-mediated DDAH1/ADMA/NO signal pathway plays an important role in TNF-α-induced endothelial dysfunction, and DMY attenuated endothelial dysfunction induced by TNF-α in a miR-21-dependent manner.

Dihydromyricetin inhibits cell proliferation, migration, invasion and promotes apoptosis via regulating miR-21 in Human Cholangiocarcinoma Cells

“…However, recent studies by Yang et al found that dihydromyricietin administration significantly restored the abnormal upregulation of miR-34a and ameliorated renal fibrosis in model mice [27]. Moreover, our previous study has shown that dihydromyricetin attenuates TNF-alpha-induced endothelial dysfunction through regulating miR-21 in HUVEC cells [10]. These studies indicate that regulating miRNA is an important mechanism of dihydromyricetin to exert its biological activities.…”

“…Natural products have been attracting huge attention due to their broad biological activities with satisfying safety in human health care used as functional foods, health products or medicine. Dihydromyricetin, the main natural product isolated from the plant Ampelopsis grossedentata, has been widely investigated and shows a variety of biological functions, including ameliorating nonalcoholic fatty liver disease 14 , anti-diabetes 15 and anti-atherosclerosis 10 . In recent years, accumulating in vitro and in vivo studies have been conducted to explore its broad anti-tumor effects 5 , 6 .…”

“…Recent studies indicate that miR-21 may be a potential diagnostic and prognostic biomarker for CCA [8,9]. As our previous study found that dihydromyricetin had great anti-atherosclerosis effects though regulating miR-21 [10], we were interested to investigate whether dihydromyricetin could exert anti-tumor effects in human CCA cell lines, and whether the underlying mechanism was through regulating miR-21. Our study might provide a possible strategy for the treatment of CCA.…”

Dihydromyricetin Improves Endothelial Dysfunction in Diabetic Mice via Oxidative Stress Inhibition in a SIRT3-Dependent Manner

“…DHY has been also proven to attenuate atherosclerosis via improving endothelial dysfunction or through microRNA-21 [ 45 , 46 ] and to protect against ligation-induced carotid artery neointimal formation [ 47 ]. In addition, DHY attenuated TNF-α-induced endothelial dysfunction [ 48 ]. Taken together, DHY improved vascular endothelial function.…”

Bioactive Ingredients in Chinese Herbal Medicines That Target Non-coding RNAs: Promising New Choices for Disease Treatment

“…The original herb has effects of detoxification, anti-inflammatory and analgesic, commonly used as a dietary supplement. DHM is now demonstrated to impede atherosclerotic process by regulating endothelial dysfunction (Yang D. et al, 2018), and exert anti-aging effect against neurodegenerative diseases (Kou et al, 2016). It inhibits miR-21 expression and then improves endothelial dysfunction induced by TNF-α, accompanied by suppression of abnormal expression of eNOS, DDAH1, NO, and ADMA, as well as improvement of tube formation and migration.…”