Disruption of Nrf2 synergizes with high glucose to cause heightened myocardial oxidative stress and severe cardiomyopathy in diabetic mice

Details

• Personal Author:
  He X ; Ma Q
• Description:
  High glucose-induced oxidative stress is a major contributing mechanism to the development of diabetic cardiomyopathy. Nrf2 is an emerging critical regulator of cellular defense against oxidative damage. The role of Nrf2 in diabetic cardiomyopathy was investigated in vivo. Streptozotocin (STZ) induced diabetes in Nrf2 knockout (KO) mice that rapidly progressed to severe conditions with high mortality within two weeks of injection; whereas, in wild type (WT) mice, diabetes was less severe with no death. Severe myocardial lesions were observed in diabetic KO mice that had high, sublethal levels of blood glucose including: (a) irregular myocardial arrangements, myofibrillar discontinuation, and cell death; (b) reduced electron density, discontinuation of myocardial fibers, and mitochondrial damage; and (c) markedly reduced contractility of the cardiomyocytes to beta-agonist stimulation. Parallel to severe cardiomyopathy, the diabetic KO hearts showed: (a) increased apoptosis as revealed by TUNEL and PARP1 cleavage assays; (b) infiltration of granulocytes and macrophages as well as fibrosis indicating robust inflammatory response; and (c) heightened oxidative stress as evidenced by increased levels of 8-hydroxydeoxyquanine, free malondialdehyde, and 3-nitrotyrosine. Increased oxidative stress in the KO hearts was attributed to decrease or loss of the basal and induced expression of Nrf2-dependent cytoprotective genes. Our findings demonstrate that loss of Nrf2 function synergizes with high glucose to cause heightened oxidative stress in the heart leading to severe diabetic cardiomyopathy. [Description provided by NIOSH]
• Subjects:
  Biological Assay Blood Cardiovascular System Cytology Fibrosis Hematologic Diseases Laboratories Mortality Occupational Health Safety
• Keywords:
  Bioassays Blood-sugar-disorders Cardiovascular-function Cardiovascular-system Cell-alteration Cell-damage Cellular-function Heart In-vivo-study Laboratory-animals Mortality-rates Myocardial-disorders Oxidative-processes Synergism

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• ISSN:
  2155-6156
• Document Type:
  Text
• Genre:
  Journal Article
• Place as Subject:
  OSHA Region 3 ; West Virginia
• CIO:
  National Institute for Occupational Safety and Health (NIOSH)
• Division:
  HELD - Health Effects Laboratory Division
• Topic:
  Workplace Safety & Health
• Location:
  North America
• Volume:
  4
• Issue:
  7
• NIOSHTIC Number:
  nn:20041271
• Citation:
  J Diabetes Metab 2013 Sep; 4(7):002
• Contact Point Address:
  Qiang Ma, NIOSH/HELD, Mailstop 3014, 1095 Willowdale Rd., Morgantown, WV 26505, USA
• Email:
  qam1@cdc.gov
• Federal Fiscal Year:
  2013
• Peer Reviewed:
  False
• Source Full Name:
  Journal of Diabetes & Metabolism
• Collection(s):
  National Institute for Occupational Safety and Health
• Main Document Checksum:
  urn:sha-512:1fc4926c6ca9f98fdf3723849b99a81635335351911870102b2ae1c0a8339c4154b9d58e54e65e4f18b4f5992dcf33d1d8bd158ddfa72dc44453004bdae6d123
• Download URL:
  https://stacks.cdc.gov/view/cdc/193874/cdc_193874_DS1.pdf
• File Type:
  [PDF - 2.62 MB ]