Hyperglycemia (HG) stimulates the production of reactive oxygen species in the heart through activation of NADPH oxidase 2 (NOX2). This production is independent of glucose metabolism but requires sodium/glucose cotransporters (SGLT). Seven SGLT isoforms (SGLT1 to 6 and sodium-myoinositol cotransporter-1, SMIT1) are known, although their expression and function in the heart remain elusive. We investigated these 7 isoforms and found that only SGLT1 and SMIT1 were expressed in mouse, rat and human hearts. In cardiomyocytes, galactose (transported through SGLT1) did not activate NOX2. Accordingly, SGLT1 deficiency did not prevent HG-induced NOX2 activation, ruling it out in the cellular response to HG. In contrast, myo-inositol (transported through SMIT1) reproduced the toxic effects of HG. SMIT1 overexpression exacerbated glucotoxicity and sensitized cardiomyocytes to HG, whereas its deletion prevented HG-induced NOX2 activation. In conclusion, our results show that heart SMIT1 senses HG and triggers NOX2 activation. This could participate in the redox signaling in hyperglycemic heart and contribute to the pathophysiology of diabetic cardiomyopathy.
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This work was funded by grants from the Fonds National de la Recherche Scientifique et Médicale (FNRS, Belgium), ‘Action de Recherche Concertée de la Communauté Wallonie-Bruxelles, Belgium (ARC 13/18-051), Société Francophone du diabète (SFD) and unrestricted grants form Astra Zeneca. FD’s work was also supported by NIH (R01HL118474, R01AG053999), Alzheimer’s Association (VMF-15-363458) and AHA/ASA (16GRNT310200) and SD’s work by NIH (R01HL109501). AVS was supported by the Fund for Scientific Research in Industry and Agriculture (FRIA), Bourse du Patrimoine (UCL, Belgium) and ARC. MB was supported by FNRS and ARC.
Supplementary information accompanies this paper at http://www.nature.com/srep
Van Steenbergen, Anne; Balteau, Magali; Ginion, Audrey; Ferté, Laura; Battault, Sylvain; de Meester de Ravenstein, Christophe; Balligand, Jean-Luc; Daskalopoulos, Evangelos-Panagiotis; Gilon, Patrick; Despa, Florin; Despa, Sanda; Vanoverschelde, Jean-Louis; Horman, Sandrine; Koepsell, Hermann; Berry, Gerard; Hue, Louis; Bertrand, Luc; and Beauloye, Christophe, "Sodium-Myoinositol Cotransporter-1, SMIT1, Mediates the Production of Reactive Oxygen Species Induced by Hyperglycemia in the Heart" (2017). Pharmacology and Nutritional Sciences Faculty Publications. 60.