NADPH oxidase activation by hyperglycaemia in cardiomyocytes is independent of glucose metabolism but requires SGLT1

Magali Balteau, Nicolas Tajeddine, Carole De Meester, Audrey Ginion, Christine Des Rosiers, Nathan R. Brady, Caroline Sommereyns, Sandrine Horman, Jean Louis Vanoverschelde, Philippe Gailly, Louis Hue, Luc Bertrand, Christophe Beauloye

Research output: Contribution to journalArticlepeer-review

Abstract

AimsExposure to high glucose (HG) stimulates reactive oxygen species (ROS) production by NADPH oxidase in cardiomyocytes, but the underlying mechanism remains elusive. In this study, we have dissected the link between glucose transport and metabolism and NADPH oxidase activation under hyperglycaemic conditions.Methods and resultsPrimary cultures of adult rat cardiomyocytes were exposed to HG concentration (HG, 21 mM) and compared with the normal glucose level (LG, 5 mM). HG exposure activated Rac1GTP and induced p47phox translocation to the plasma membrane, resulting in NADPH oxidase (NOX2) activation, increased ROS production, insulin resistance, and eventually cell death. Comparison of the level of O-linked N-acetylglucosamine (O-GlcNAc) residues in LG-and HG-treated cells did not reveal any significant difference. Inhibition of the pentose phosphate pathway (PPP) by 6-aminonicotinamide counteracted ROS production in response to HG but did not prevent Rac-1 upregulation and p47phox translocation leading to NOX2 activation. Modulation of glucose uptake barely affected oxidative stress and toxicity induced by HG. More interestingly, non-metabolizable glucose analogues (i.e. 3-O-methyl-d-glucopyranoside and α-methyl-d-glucopyranoside) reproduced the toxic effect of HG. Inhibition of the sodium/glucose cotransporter SGLT1 by phlorizin counteracted HG-induced NOX2 activation and ROS production. ConclusionIncreased glucose metabolism by itself does not trigger NADPH oxidase activation, although PPP is required to provide NOX2 with NADPH and to produce ROS. NOX2 activation results from glucose transport through SGLT1, suggesting that an extracellular metabolic signal transduces into an intracellular ionic signal.

Original languageEnglish (US)
Pages (from-to)237-246
Number of pages10
JournalCardiovascular research
Volume92
Issue number2
DOIs
StatePublished - Nov 1 2011
Externally publishedYes

Keywords

  • Glucose metabolism
  • Glucotoxicity
  • NADPH oxidase
  • Oxidative stress
  • SGLT

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

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