Adaptive induction of NF‐E2–Related Factor‐2‐driven antioxidant genes in endothelial cells in response to hyperglycemia

Abstract

Hyperglycemia in diabetes mellitus elicits vascular oxidative stress promoting the development of cardiovascular diseases. Nrf2 is a redox-sensitive transcription factor that regulates expression of numerous antioxidant enzymes. The present study was designed to elucidate the homeostatic role of adaptive induction of Nrf2-driven free radical detoxification mechanisms in endothelial protection under diabetic conditions. We found that in cultured coronary arterial endothelial cells hyperglycemia activated Nrf2 and up-regulated the expression of the Nrf2 target genes NQO1, GCLC and HMOX1. These effects were significantly attenuated by siRNA knockdown of Nrf2, overexpression of Keap-1 (which inactivates Nrf2) or by pre-treatment with PEG-catalase and N-acetylcysteine, whereas administration of H2O2 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). The HFD elicited significant increases in mRNA expression of Gclc and Hmox1 in aortas of Nrf2+/+ mice but not in vessels of Nrf2−/− mice, as compared to the respective standard diet-fed controls. Additionally, HFD-induced oxidative stress and endothelial dysfunction were more severe in Nrf2−/− mice, as compared to Nrf2+/+ mice. Thus, adaptive activation of the Nrf2/ARE pathway confers endothelial protection under diabetic conditions. (Funding: ADA, AFAR, NIH).