Adaptive induction of NF-E2-related factor-2-driven antioxidant genes in endothelial cells in response to hyperglycemia

Zoltan Ungvari, Lora Bailey-Downs, Tripti Gautam, Rosario Jimenez, Gyorgy Losonczy, Cuihua Zhang, Praveen Ballabh, Fabio A. Recchia, Donald C. Wilkerson, William E. Sonntag, Kevin Pearson, Rafael de Cabo, Anna Csiszar

Research output: Contribution to journalArticle

98 Citations (Scopus)

Abstract

Hyperglycemia in diabetes mellitus promotes oxidative stress in endothelial cells, which contributes to development of cardiovascular diseases. Nuclear factor erythroid 2-related factor-2 (Nrf2) is a transcription factor activated by oxidative stress that regulates expression of numerous reactive oxygen species (ROS) detoxifying and antioxidant genes. This study was designed to elucidate the homeostatic role of adaptive induction of Nrf2-driven free radical detoxification mechanisms in endothelial protection under diabetic conditions. Using a Nrf2/antioxidant response element (ARE)-driven luciferase reporter gene assay we found that in a cultured coronary arterial endothelial cell model hyperglycemia (10-30 mmol/l glucose) significantly increases transcriptional activity of Nrf2 and upregulates the expression of the Nrf2 target genes NQO1, GCLC, and HMOX1. These effects of high glucose were significantly attenuated by small interfering RNA (siRNA) downregulation of Nrf2 or overexpression of Keap-1, which inactivates Nrf2. High-glucose-induced upregulation of NQO1, GCLC, and HMOX1 was also prevented by pretreatment with polyethylene glycol (PEG)-catalase or N-acetylcysteine, whereas administration of H 2O 2 mimicked the effect of high glucose. To test the effects of metabolic stress in vivo, Nrf2 +/+ and Nrf2 -/- mice were fed a high-fat diet (HFD). HFD elicited significant increases in mRNA expression of Gclc and Hmox1 in aortas of Nrf2 +/+ mice, but not Nrf2 -/- mice, compared with respective standard diet-fed control mice. Additionally, HFD-induced increases in vascular ROS levels were significantly greater in Nrf2 -/- than Nrf2 +/+ mice. HFD-induced endothelial dysfunction was more severe in Nrf2 -/- mice, as shown by the significantly diminished acetylcholine-induced relaxation of aorta of these animals compared with HFD-fed Nrf2 +/+ mice. Our results suggest that adaptive activation of the Nrf2/ARE pathway confers endothelial protection under diabetic conditions.

Original languageEnglish (US)
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume300
Issue number4
DOIs
StatePublished - Apr 2011
Externally publishedYes

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NF-E2-Related Factor 2
Hyperglycemia
Endothelial Cells
High Fat Diet
Antioxidants
Genes
Antioxidant Response Elements
Glucose
Aorta
Reactive Oxygen Species
Oxidative Stress
Up-Regulation
Physiological Stress
Acetylcysteine
Luciferases
Reporter Genes
Small Interfering RNA
Acetylcholine
Free Radicals
Blood Vessels

Keywords

  • Diabetes
  • Endothelial dysfunction
  • Oxidative stress

ASJC Scopus subject areas

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

Cite this

Adaptive induction of NF-E2-related factor-2-driven antioxidant genes in endothelial cells in response to hyperglycemia. / Ungvari, Zoltan; Bailey-Downs, Lora; Gautam, Tripti; Jimenez, Rosario; Losonczy, Gyorgy; Zhang, Cuihua; Ballabh, Praveen; Recchia, Fabio A.; Wilkerson, Donald C.; Sonntag, William E.; Pearson, Kevin; de Cabo, Rafael; Csiszar, Anna.

In: American Journal of Physiology - Heart and Circulatory Physiology, Vol. 300, No. 4, 04.2011.

Research output: Contribution to journalArticle

Ungvari, Z, Bailey-Downs, L, Gautam, T, Jimenez, R, Losonczy, G, Zhang, C, Ballabh, P, Recchia, FA, Wilkerson, DC, Sonntag, WE, Pearson, K, de Cabo, R & Csiszar, A 2011, 'Adaptive induction of NF-E2-related factor-2-driven antioxidant genes in endothelial cells in response to hyperglycemia', American Journal of Physiology - Heart and Circulatory Physiology, vol. 300, no. 4. https://doi.org/10.1152/ajpheart.00402.2010
Ungvari, Zoltan ; Bailey-Downs, Lora ; Gautam, Tripti ; Jimenez, Rosario ; Losonczy, Gyorgy ; Zhang, Cuihua ; Ballabh, Praveen ; Recchia, Fabio A. ; Wilkerson, Donald C. ; Sonntag, William E. ; Pearson, Kevin ; de Cabo, Rafael ; Csiszar, Anna. / Adaptive induction of NF-E2-related factor-2-driven antioxidant genes in endothelial cells in response to hyperglycemia. In: American Journal of Physiology - Heart and Circulatory Physiology. 2011 ; Vol. 300, No. 4.
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