Dietary ellagic acid improves oxidant-induced endothelial dysfunction and atherosclerosis: role of Nrf2 activation

Int J Cardiol. 2014 Aug 20;175(3):508-14. doi: 10.1016/j.ijcard.2014.06.045. Epub 2014 Jul 2.


Background: Oxidative stress-induced vascular endothelial cell injury is a major factor in the pathogenesis of atherosclerosis. Several evidences indicate that ellagic acid (EA), a phenolic compound, contributes to cardiovascular health. This study was to investigate the effects of EA on endothelial dysfunction and atherosclerosis via antioxidant-related mechanisms.

Methods: In animal studies, wild-type (WT) C57BL/6 mice and apolipoprotein E-deficient mice (ApoE(-/-)) mice were fed: a high-fat (21%) diet (HFD) or a HFD plus with EA (HFD+EA), for 14weeks. Vascular reactivity was studied in mice aortas. The effect of EA in human umbilical vein endothelial cells (HAECs) exposed to hypochlorous acid (HOCl) was also investigated.

Results: Compared with animals on HFD alone, EA attenuated atherosclerosis in WT mice. In aortic rings from two mice models, EA significantly improved endothelium-dependent relaxation and attenuated HOCl-induced endothelial dysfunction. Besides, EA significantly improved nitric oxide synthase activity, antioxidant capacity and markers of endothelial dysfunction in plasma. Western blot analysis showed that EA increased NF-E2-related factor 2 (Nrf2) and heme oxygenase-1(HO-1) expression in the aortas (P<0.05). In a separate experiment, EA did not protect against HOCl-induced endothelial dysfunction in arteries obtained from Nrf2 gene knockout mice compared with WT mice. In HAECs, EA prevented HOCl-induced cellular damage and induced HO-1 protein expression, and these effects markedly abolished by the siRNA of Nrf2.

Conclusions: Our results provide further support for the protective effects of dietary EA particularly oxidant-induced endothelial dysfunction and atherosclerosis partly via Nrf2 activation.

Keywords: Atherosclerosis; Endothelial dysfunction; Oxidative stress.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Arteriosclerosis / chemically induced
  • Arteriosclerosis / diet therapy*
  • Arteriosclerosis / metabolism*
  • Diet, High-Fat / adverse effects
  • Ellagic Acid / administration & dosage*
  • Endothelium, Vascular / drug effects
  • Endothelium, Vascular / metabolism*
  • Human Umbilical Vein Endothelial Cells / drug effects
  • Human Umbilical Vein Endothelial Cells / metabolism
  • Humans
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • NF-E2-Related Factor 2 / metabolism*
  • Organ Culture Techniques
  • Oxidants / toxicity*
  • Random Allocation


  • NF-E2-Related Factor 2
  • Nfe2l2 protein, mouse
  • Oxidants
  • Ellagic Acid