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

Authors
He-X; Kan-H; Cai-L; Ma-Q
Source
J Mol Cell Cardiol 2009 Jan; 46(1):47-58
NIOSHTIC No.
20034762
Abstract
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.
Keywords
Cardiac-function; Cardiovascular-system-disease; Cardiovascular-system-disorders; Genes; Genetic-factors; Genetics; Myocardial-disorders; Myocardium; Cell-biology; Cell-function; Cellular-reactions; Antioxidants; Antioxidation; Author Keywords: Nrf2; Diabetic cardiomyopathy; Reactive oxygen species; Oxidative stress; Antioxidant; Glucose
Contact
Qiang Ma, National Institute for Occupational Safety and Health, CDC, Receptor Biology Laboratory, TMBB, HELD, MS 3014, 1095 Willowdale Road, Morgantown, WV 26505; Lu Cai, Dept. of Medicine, Shool of Medicine, Univ. of Louisville, Louistille, KY 40202
CODEN
JMCDAY
Publication Date
20090101
Document Type
Journal Article
Email Address
qam1@cdc.gov; 10cai001@louisville.edu
Fiscal Year
2009
NTIS Accession No.
NTIS Price
Issue of Publication
1
ISSN
0022-2828
NIOSH Division
HELD
Source Name
Journal of Molecular and Cellular Cardiology
State
WV; KY
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