TY - JOUR
T1 - Sodium-myoinositol cotransporter-1, SMIT1, mediates the production of reactive oxygen species induced by hyperglycemia in the heart
AU - Van Steenbergen, Anne
AU - Balteau, Magali
AU - Ginion, Audrey
AU - Ferté, Laura
AU - Battault, Sylvain
AU - Ravenstein, Christophe De Meester De
AU - Balligand, Jean Luc
AU - Daskalopoulos, Evangelos Panagiotis
AU - Gilon, Patrick
AU - Despa, Florin
AU - Despa, Sanda
AU - Vanoverschelde, Jean Louis
AU - Horman, Sandrine
AU - Koepsell, Hermann
AU - Berry, Gerard
AU - Hue, Louis
AU - Bertrand, Luc
AU - Beauloye, Christophe
N1 - Publisher Copyright:
© 2017 The Author(s).
PY - 2017/1/27
Y1 - 2017/1/27
N2 - 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.
AB - 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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U2 - 10.1038/srep41166
DO - 10.1038/srep41166
M3 - Article
C2 - 28128227
AN - SCOPUS:85010903512
SN - 2045-2322
VL - 7
JO - Scientific Reports
JF - Scientific Reports
M1 - 41166
ER -
