Nrf2 is critical in defense against high glucose-induced oxidative damage in cardiomyocytes

Author(s): He X, Kan H, Cai L, Ma Q


Exposure to high levels of glucose induces the production of reactive oxygen species (ROS) in cardiomyocytes that may contribute to the development of cardiomyopathy in diabetes. Nuclear factor erythroid 2-related factor 2 (Nrf2) controls the antioxidant response element (ARE)-dependent gene regulation in response to oxidative stress. The role of Nrf2 in defense against high glucose-induced oxidative damage in cardiomyocytes was investigated. Glucose at high concentrations induced ROS production in both primary neonatal and adult cardiomyocytes from the Nrf2 wild type (WT) mouse heart, whereas, in Nrf2 knockout (KO) cells, ROS was significantly higher under basal conditions and high glucose markedly further increased ROS production in concentration and time-dependent manners. Concomitantly, high glucose induced significantly higher levels of apoptosis at lower concentrations and in shorter time in Nrf2 KO cells than in WT cells. Primary adult cardiomyocytes from control and diabetic mice also showed dependence on Nrf2 function for isoproterenol-stimulated contraction. Additionally, cardiomyocytes from Nrf2 KO mice exhibited increased sensitivity to 3-nitropropionic acid, an inhibitor of mitochondrial respiratory complex II, for both ROS production and apoptosis compared with Nrf2 WT cells, further emphasizing the role of Nrf2 in ROS defense in the cells. Mechanistically, Nrf2 was shown to mediate the basal expression and induction of ARE-controlled cytoprotective genes, Nqo1 and Ho1, at both mRNA and protein levels in cardiomyocytes, as both the basal and inducible expressions of the genes were lost in Nrf2 KO cells or largely reduced by Nrf2 SiRNA. The findings, for the first time, established Nrf2 as a critical regulator of defense against ROS in normal and diabetic hearts.

Similar Articles

Global and societal implications of the diabetes epidemic

Author(s): Zimmet P, Alberti KG, Shaw J

Diabetic cardiomyopathy

Author(s): Murarka S, Movahed MR

Diabetic cardiomyopathy--a distinct disease? Best Pract Res Clin Endocrinol Metab 23: 347-360

Author(s): Khavandi K, Khavandi A, Asghar O, Greenstein A, Withers S, et al.

Oxidative stress and diabetic complications

Author(s): Giacco F, Brownlee M

Vacuolar leukoencephalopathy with widespread astrogliosis in mice lacking transcription factor Nrf2

Author(s): Hubbs AF, Benkovic SA, Miller DB, O'Callaghan JP, Battelli L, et al.

The transcription factor NRF2 protects against pulmonary fibrosis

Author(s): Cho HY, Reddy SP, Yamamoto M, Kleeberger SR