title: Sodium-myoinositol cotransporter-1, SMIT1, mediates the production of reactive oxygen species induced by hyperglycemia in the heart.
abstract: 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.
authors.affiliation: Université catholique de Louvain, Institut de Recherche Expérimentale et Clinique, Pôle de Recherche Cardiovasculaire, Brussels, Belgium.
authors.forename: Anne
authors.initials: A
authors.lastname: Van Steenbergen
authors.affiliation: Université catholique de Louvain, Institut de Recherche Expérimentale et Clinique, Pôle de Recherche Cardiovasculaire, Brussels, Belgium.
authors.forename: Magali
authors.initials: M
authors.lastname: Balteau
authors.affiliation: Université catholique de Louvain, Institut de Recherche Expérimentale et Clinique, Pôle de Recherche Cardiovasculaire, Brussels, Belgium.
authors.forename: Audrey
authors.initials: A
authors.lastname: Ginion
authors.affiliation: Université catholique de Louvain, Institut de Recherche Expérimentale et Clinique, Pôle de Recherche Cardiovasculaire, Brussels, Belgium.
authors.forename: Laura
authors.initials: L
authors.lastname: Ferté
authors.affiliation: Université catholique de Louvain, Institut de Recherche Expérimentale et Clinique, Pôle de Recherche Cardiovasculaire, Brussels, Belgium.
authors.forename: Sylvain
authors.initials: S
authors.lastname: Battault
authors.affiliation: Université catholique de Louvain, Institut de Recherche Expérimentale et Clinique, Pôle de Recherche Cardiovasculaire, Brussels, Belgium.
authors.forename: Christophe de Meester de
authors.initials: CM
authors.lastname: Ravenstein
authors.affiliation: Université catholique de Louvain, Institut de Recherche Expérimentale et Clinique, Pole of Pharmacology and Therapeutics, Brussels, Belgium.|Cliniques Universitaires Saint-Luc, Department of Medicine, Brussels, Belgium.
authors.forename: Jean-Luc
authors.initials: JL
authors.lastname: Balligand
authors.affiliation: Université catholique de Louvain, Institut de Recherche Expérimentale et Clinique, Pôle de Recherche Cardiovasculaire, Brussels, Belgium.
authors.forename: Evangelos-Panagiotis
authors.initials: EP
authors.lastname: Daskalopoulos
authors.affiliation: Université Catholique de Louvain, Institut de Recherche Expérimentale et Clinique, Pôle d'Endocrinologie, Diabète et Nutrition, Brussels, Belgium.
authors.forename: Patrick
authors.initials: P
authors.lastname: Gilon
authors.affiliation: University of Kentucky, Department of Pharmacology and Nutritional Sciences, Lexington, KY, USA.
authors.forename: Florin
authors.initials: F
authors.lastname: Despa
authors.affiliation: University of Kentucky, Department of Pharmacology and Nutritional Sciences, Lexington, KY, USA.
authors.forename: Sanda
authors.initials: S
authors.lastname: Despa
authors.affiliation: Université catholique de Louvain, Institut de Recherche Expérimentale et Clinique, Pôle de Recherche Cardiovasculaire, Brussels, Belgium.|Cliniques Universitaires Saint Luc, Division of Cardiology, Brussels, Belgium.
authors.forename: Jean-Louis
authors.initials: JL
authors.lastname: Vanoverschelde
authors.affiliation: Université catholique de Louvain, Institut de Recherche Expérimentale et Clinique, Pôle de Recherche Cardiovasculaire, Brussels, Belgium.
authors.forename: Sandrine
authors.initials: S
authors.lastname: Horman
authors.affiliation: University of Würzburg, Department of Molecular Plant Physiology and Biophysics, Julius von Sachs Institute, Würzburg, Germany.
authors.forename: Hermann
authors.initials: H
authors.lastname: Koepsell
authors.affiliation: Harvard Medical School, Children's Hospital Boston, Division of Genetics and Genomics, Department of Pediatrics, Boston, MA, USA.
authors.forename: Gerard
authors.initials: G
authors.lastname: Berry
authors.affiliation: Université catholique de Louvain, Institut de Recherche Expérimentale et Clinique, Pôle de Recherche Cardiovasculaire, Brussels, Belgium.|Université catholique de Louvain, de Duve Institute, Brussels, Belgium.
authors.forename: Louis
authors.initials: L
authors.lastname: Hue
authors.affiliation: Université catholique de Louvain, Institut de Recherche Expérimentale et Clinique, Pôle de Recherche Cardiovasculaire, Brussels, Belgium.
authors.forename: Luc
authors.initials: L
authors.lastname: Bertrand
authors.affiliation: Université catholique de Louvain, Institut de Recherche Expérimentale et Clinique, Pôle de Recherche Cardiovasculaire, Brussels, Belgium.|Cliniques Universitaires Saint Luc, Division of Cardiology, Brussels, Belgium.
authors.forename: Christophe
authors.initials: C
authors.lastname: Beauloye
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D055786:Gene Knockout Techniques; D006360:Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D006943:Hyperglycemia / Q000378:metabolism*; D008297:Male; D051379:Mice; D009206:Myocardium / Q000378:metabolism*; D000074662:NADPH Oxidase 2 / Q000378:metabolism*; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism*; D051269:Sodium-Glucose Transporter 1; D027981:Symporters / Q000235:genetics / Q000378:metabolism*
chemical_list: D006360:Heat-Shock Proteins; D017382:Reactive Oxygen Species; C495674:SLC5A1 protein, human; D051269:Sodium-Glucose Transporter 1; D027981:Symporters; C073884:SLC5A3 protein, human; C056558:CYBB protein, human; D000074662:NADPH Oxidase 2