Dihydromyricetin ameliorates atherosclerosis in LDL receptor deficient mice

Atherosclerosis. 2017 Jul:262:39-50. doi: 10.1016/j.atherosclerosis.2017.05.003. Epub 2017 May 5.

Abstract

Background and aims: Dihydromyricetin, the most abundant flavonoid in Ampelopsis grossedentata, exerts numerous pharmacological activities, including anti-inflammatory, antioxidant, hepatoprotective, and lipid regulatory activities; however, its protective effect against atherosclerosis remains poorly understood. The aim of the present study was to evaluate the effects of dihydromyricetin on high fat diet (HFD)-induced atherosclerosis using LDL receptor deficient (LDLr-/-) mice.

Methods: Blood samples were collected for determination of serum lipid profiles, oxidized LDL (ox-LDL) and pro-inflammatory cytokines. Histology, hepatic lipid content, quantification of atherosclerosis, assessment of oxidative stress and inflammation were performed on liver and aorta samples by molecular biology methods. The effects of dihydromyricetin on ox-LDL-induced human umbilical vein endothelial cells (HUVECs) dysfunction and foam cell formation were further studied.

Results: (1) Dihydromyricetin ameliorated hyperlipidemia, reduced serum ox-LDL, IL-6 and TNF-α levels in HFD-fed LDLr-/- mice. Moreover, (2) dihydromyricetin suppressed hepatic lipid accumulation and increased protein expressions of PPARα, LXRα and ABCA1. (3) It inhibited atherosclerotic lesion formation and favoured features of plaque stability. (4) Dihydromyricetin prevented hepatic and aortic inflammation as evidenced by the reduced IL-6 and TNF-α mRNA expression; (5) it prevented hepatic and aortic oxidative stress by normalizing activities of antioxidant enzymes in the liver and suppressing reactive oxygen species generation and NOX2 protein expression in both liver and aorta; (6) it inhibited oxLDL-induced injury, monocytes adhesion and oxidative stress in HUVECs and (7) inhibited macrophage foam cell formation and enhanced cholesterol efflux.

Conclusions: These findings suggest that dihydromyricetin could reduce atherosclerosis via its pleiotropic effects, including improvement of endothelial dysfunction, inhibition of macrophage foam cell formation, amelioration of lipid profiles, anti-inflammatory action and anti-oxidative effect.

Keywords: Anti-inflammation; Anti-oxidation; Atherosclerosis; Dihydromyricetin.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anti-Inflammatory Agents / pharmacology*
  • Antioxidants / pharmacology*
  • Aorta / drug effects*
  • Aorta / metabolism
  • Aorta / pathology
  • Aortic Diseases / genetics
  • Aortic Diseases / metabolism
  • Aortic Diseases / pathology
  • Aortic Diseases / prevention & control*
  • Atherosclerosis / genetics
  • Atherosclerosis / metabolism
  • Atherosclerosis / pathology
  • Atherosclerosis / prevention & control*
  • Cytokines / blood
  • Diet, High-Fat
  • Disease Models, Animal
  • Flavonols / pharmacology*
  • Foam Cells / drug effects
  • Foam Cells / metabolism
  • Foam Cells / pathology
  • Genetic Predisposition to Disease
  • Human Umbilical Vein Endothelial Cells / drug effects
  • Human Umbilical Vein Endothelial Cells / metabolism
  • Human Umbilical Vein Endothelial Cells / pathology
  • Humans
  • Inflammation Mediators / blood
  • Lipoproteins, LDL / blood
  • Liver / drug effects
  • Liver / metabolism
  • Male
  • Mice
  • Mice, Knockout
  • Oxidative Stress / drug effects*
  • Phenotype
  • Plaque, Atherosclerotic
  • RAW 264.7 Cells
  • Receptors, LDL / deficiency*
  • Receptors, LDL / genetics

Substances

  • Anti-Inflammatory Agents
  • Antioxidants
  • Cytokines
  • Flavonols
  • Inflammation Mediators
  • Lipoproteins, LDL
  • Receptors, LDL
  • oxidized low density lipoprotein
  • dihydromyricetin