Resveratrol confers endothelial protection via activation of the antioxidant transcription factor Nrf2

Zoltan Ungvari, Zsolt Bagi, Attila Feher, Fabio A. Recchia, William E. Sonntag, Kevin Pearson, Rafael De Cabo, Anna Csiszar

Research output: Contribution to journalArticle

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Abstract

Epidemiological studies suggest that Mediterranean diets rich in resveratrol are associated with reduced risk of coronary artery disease. Resveratrol was also shown to confer vasoprotection in animal models of type 2 diabetes and aging. However, the mechanisms by which resveratrol exerts its antioxidative vasculoprotective effects are not completely understood. Using a nuclear factor-E2-related factor-2 (Nrf2)/antioxidant response element-driven luciferase reporter gene assay, we found that in cultured coronary arterial endothelial cells, resveratrol, in a dose-dependent manner, significantly increases transcriptional activity of Nrf2. Accordingly, resveratrol significantly upregulates the expression of the Nrf2 target genes NAD(P)H:quinone oxidoreductase 1, γ-glutamylcysteine synthetase, and heme oxygenase-1. Resveratrol treatment also significantly attenuated high glucose (30 mM)-induced mitochondrial and cellular oxidative stress (assessed by flow cytometry using MitoSox and dihydroethidine staining). The aforementioned effects of resveratrol were significantly attenuated by the small interfering RNA downregulation of Nrf2 or the overexpression of Kelch-like erythroid cell-derived protein 1, which inactivates Nrf2. To test the effects of resveratrol in vivo, we used mice fed a high-fat diet (HFD), which exhibit increased vascular oxidative stress associated with an impaired endothelial function. In HFD-fed Nrf2+/+ mice, resveratrol treatment attenuates oxidative stress (assessed by the Amplex red assay), improves acetylcholine-induced vasodilation, and inhibits apoptosis (assessed by measuring caspase-3 activity and DNA fragmentation) in branches of the femoral artery. In contrast, the aforementioned endothelial protective effects of resveratrol were diminished in HFD-fed Nrf2-/- mice. Taken together, our results indicate that resveratrol both in vitro and in vivo confers endothelial protective effects which are mediated by the activation of Nrf2.

Original languageEnglish (US)
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume299
Issue number1
DOIs
StatePublished - Jul 1 2010

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NF-E2-Related Factor 2
Transcription Factors
Antioxidants
High Fat Diet
Oxidative Stress
resveratrol
Antioxidant Response Elements
Glutamate-Cysteine Ligase
Mediterranean Diet
Erythroid Cells
Heme Oxygenase-1
DNA Fragmentation
Femoral Artery
Luciferases
Reporter Genes
Vasodilation
Caspase 3
NAD
Type 2 Diabetes Mellitus
Small Interfering RNA

Keywords

  • Endothelial cell
  • Gracilis
  • Nuclear factor-E-related factor-2
  • Resveratrol

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

Cite this

Resveratrol confers endothelial protection via activation of the antioxidant transcription factor Nrf2. / Ungvari, Zoltan; Bagi, Zsolt; Feher, Attila; Recchia, Fabio A.; Sonntag, William E.; Pearson, Kevin; De Cabo, Rafael; Csiszar, Anna.

In: American Journal of Physiology - Heart and Circulatory Physiology, Vol. 299, No. 1, 01.07.2010.

Research output: Contribution to journalArticle

Ungvari, Zoltan ; Bagi, Zsolt ; Feher, Attila ; Recchia, Fabio A. ; Sonntag, William E. ; Pearson, Kevin ; De Cabo, Rafael ; Csiszar, Anna. / Resveratrol confers endothelial protection via activation of the antioxidant transcription factor Nrf2. In: American Journal of Physiology - Heart and Circulatory Physiology. 2010 ; Vol. 299, No. 1.
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AB - Epidemiological studies suggest that Mediterranean diets rich in resveratrol are associated with reduced risk of coronary artery disease. Resveratrol was also shown to confer vasoprotection in animal models of type 2 diabetes and aging. However, the mechanisms by which resveratrol exerts its antioxidative vasculoprotective effects are not completely understood. Using a nuclear factor-E2-related factor-2 (Nrf2)/antioxidant response element-driven luciferase reporter gene assay, we found that in cultured coronary arterial endothelial cells, resveratrol, in a dose-dependent manner, significantly increases transcriptional activity of Nrf2. Accordingly, resveratrol significantly upregulates the expression of the Nrf2 target genes NAD(P)H:quinone oxidoreductase 1, γ-glutamylcysteine synthetase, and heme oxygenase-1. Resveratrol treatment also significantly attenuated high glucose (30 mM)-induced mitochondrial and cellular oxidative stress (assessed by flow cytometry using MitoSox and dihydroethidine staining). The aforementioned effects of resveratrol were significantly attenuated by the small interfering RNA downregulation of Nrf2 or the overexpression of Kelch-like erythroid cell-derived protein 1, which inactivates Nrf2. To test the effects of resveratrol in vivo, we used mice fed a high-fat diet (HFD), which exhibit increased vascular oxidative stress associated with an impaired endothelial function. In HFD-fed Nrf2+/+ mice, resveratrol treatment attenuates oxidative stress (assessed by the Amplex red assay), improves acetylcholine-induced vasodilation, and inhibits apoptosis (assessed by measuring caspase-3 activity and DNA fragmentation) in branches of the femoral artery. In contrast, the aforementioned endothelial protective effects of resveratrol were diminished in HFD-fed Nrf2-/- mice. Taken together, our results indicate that resveratrol both in vitro and in vivo confers endothelial protective effects which are mediated by the activation of Nrf2.

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