Reactive oxygen species mediate a cellular 'memory' of high glucose stress signalling

M. A. Ihnat, J. E. Thorpe, C. D. Kamat, C. Szabó, D. E. Green, L. A. Warnke, Z. Lacza, A. Cselenyák, K. Ross, S. Shakir, L. Piconi, R. C. Kaltreider, A. Ceriello

Research output: Contribution to journalArticlepeer-review

185 Scopus citations


Aims/hypothesis: A long-term 'memory' of hyperglycaemic stress, even when glycaemia is normalised, has been previously reported in endothelial cells. In this report we sought to duplicate and extend this finding. Materials and methods: HUVECs and ARPE-19 retinal cells were incubated in 5 or in 30 mmol/l glucose for 3 weeks or subjected to 1 week of normal glucose after being exposed for 2 weeks to continuous high glucose. HUVECs were also treated in this last condition with several antioxidants. Similarly, four groups of rats were studied for 3 weeks: (1) normal rats; (2) diabetic rats not treated with insulin; (3) diabetic rats treated with insulin during the last week; and (4) diabetic rats treated with insulin plus α-lipoic acid in the last week. Results: In human endothelial cells and ARPE-19 retinal cells in culture, as well as in the retina of diabetic rats, levels of the following markers of high glucose stress remained induced for 1 week after levels of glucose had normalised: protein kinase C-β, NAD(P)H oxidase subunit p47phox, BCL-2-associated X protein, 3-nitrotyrosine, fibronectin, poly(ADP-ribose) Blockade of reactive species using different approaches, i.e. the mitochondrial antioxidant α-lipoic acid, overexpression of uncoupling protein 2, oxypurinol, apocynin and the poly(ADP-ribose) polymerase inhibitor PJ34, interrupted the induction both of high glucose stress markers and of the fluorescent reactive oxygen species (ROS) probe CM-H2DCFDA in human endothelial cells. Similar results were obtained in the retina of diabetic rats with α-lipoic acid added to the last week of normalised glucose. Conclusions/interpretation: These results provide proof-of-principle of a ROS-mediated cellular persistence of vascular stress after glucose normalisation.

Original languageEnglish (US)
Pages (from-to)1523-1531
Number of pages9
Issue number7
StatePublished - Jul 2007
Externally publishedYes


  • Antioxidants
  • Diabetic complications
  • Endothelial cells
  • Endothelial dysfunction
  • Hyperglycaemia
  • Memory
  • Oxidative stress
  • Retinal cells
  • Retinopathy

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism


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