Induction of HO-1 and redox signaling in endothelial cells by advanced glycation end products: a role for Nrf2 in vascular protection in diabetes.
OBJECTIVE
Hyperglycemia and diabetes are associated with increased formation of advanced glycation end products and enhanced oxidative stress, leading to the progression of diabetic vascular disease. We have investigated the mechanisms by which AGE-modified bovine albumin (AGE-BSA) induces reactive oxygen species (ROS) generation, leading to nuclear factor-erythroid 2-related factor (Nrf2) dependent induction of the antioxidant genes heme oxygenase-1 (HO-1) and NADPH:quinone oxidoreductase 1 (NQO1) in bovine aortic endothelial cells.


RESULTS
AGE-BSA (100 μg ml⁻¹, 0-24 h), but not native BSA, elicited time-dependent increases in ROS generation, Nrf2 nuclear translocation and enhanced mRNA and protein expression of HO-1 and NQO1, but not glutathione peroxidase-1. Inhibition of ROS production with the superoxide scavenger Tiron or inhibitors of flavoproteins (diphenylene iodonium) and NADPH oxidase (apocynin), but not eNOS (L-NAME) or mitochondria complex I (rotenone) abrogated HO-1 induction by AGE-BSA. Although AGE-BSA induced rapid phosphorylation of JNK and Akt, only inhibition of JNK abrogated HO-1 expression, implicating the involvement of the JNK signaling pathway in AGEs activation of Nrf2/ARE-linked antioxidant gene expression.


CONCLUSIONS
Our findings establish that AGEs activate redox sensitive Nrf2-dependent antioxidant gene expression in bovine aortic endothelial cells, providing an adaptive endogenous defense against oxidative stress in diabetes.
Cardiovascular Division, School of Medicine, King's College London, 150 Stamford Street, London SE1 9NH, UK.
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Siow
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Sugden
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Gao
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Cheng
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Mann
D000818:Animals; D002417:Cattle; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D002478:Cells, Cultured; D003920:Diabetes Mellitus / Q000503:physiopathology; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D004790:Enzyme Induction / Q000187:drug effects; D016166:Free Radical Scavengers / Q000494:pharmacology; D017127:Glycation End Products, Advanced / Q000633:toxicity*; D051547:Heme Oxygenase-1 / Q000096:biosynthesis* / Q000235:genetics; D006943:Hyperglycemia / Q000503:physiopathology; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000235:genetics / Q000378:metabolism; D051267:NF-E2-Related Factor 2 / Q000819:agonists / Q000378:metabolism*; D018384:Oxidative Stress; D021381:Protein Transport / Q000187:drug effects; D012333:RNA, Messenger / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism*; D012710:Serum Albumin, Bovine / Q000633:toxicity*; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors
D016166:Free Radical Scavengers; D017127:Glycation End Products, Advanced; D051267:NF-E2-Related Factor 2; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; C081628:advanced glycation end products-bovine serum albumin; D012710:Serum Albumin, Bovine; D051547:Heme Oxygenase-1; D016660:NAD(P)H Dehydrogenase (Quinone)