Title: 0418 Sodium-glucose cotransporters (SGLT) in the heart. Contribution of SGLT-type of transport in hyperglycemia-induced signaling pathway in adult cardiomyocytes
Abstract: Exposure to hyperglycemic conditions increases reactive oxygen species (ROS) production in adult cardiomyocytes, inducing glucotoxicity. This is due to an NADPH oxidase activation and more particularly the NOX2 isoform. Our group has demonstrated that hyperglycemia-induced toxic effect does not required glucose metabolism but results from glucose transport through a SGLT type of transport. SGLT acts as glucose sensor. Seven SGLT isoforms have been described (SGLT1 to 6 and SMIT1) but their expression in the heart remains to be elucidated. The aim of this work is to study SGLT isoforms expression in the heart and identify the isoform responsible for glucotoxicity. SGLT isoforms expression has been performed in heart extracts (from rats, mice and humans) and in isolated cardiomyocytes (from rats and mice) using PCR and westernblotting. The study of the contribution of each isoforms to glucotoxicity is based on the substrates specifity of all these SGLT isoforms. SGLT1, SGLT3 and SMIT1 are expressed in the heart and in cardiomyocytes from rats and mice as well as in human heart. In human heart, SGLT3 expression is marginal. SGLT4 is only expressed in rat heart. In presence of 5 mM glucose, rat cardiomyocytes exposure to high concentration of galactose (16 mM, transported through SGLT1) does not activate NOX2. By contrast, myo-inositol (16 mM, transported through SMIT1) completly reproduces hyperglycemic effects. Indeed, it favors p47phox translocation inducing NOX2 activation and stimulates ROS production. This ROS production is blocked by a NOX2 specific inhibitor (gp91dstat). Similar observation was perfomed in mice cardiomyocytes. SGLT1 and SMIT1 are expressed in rats, mice and human cardiomyocytes. Increased transport through SMIT1 activates NOX2.