Implication of SMIT1 in ROS-dependent alteration of endothelial function during an acute hyperglycemia

Abstract

Previous investigations from our group and others revealed that hyperglycemia (HG) impairs vascular endothelial function particularly through an increased oxidative stress. For a long time, little was known about the glucose transport mechanisms responsible for these alterations in the cardiovascular system under HG conditions. However, recent work has shown the involvement of the sodium myo-inositol transporter 1 (SMIT1) of the sodium-glucose co-transporter (SGLT) family in HG-dependent ROS production. However, few studies have focused on the involvement of these transporters in the vascular effects of HG. In this context, we aimed to evaluate the implication of the different SGLT isoforms on the increased oxidative stress and the subsequent vascular dysfunction reported during HG. Firstly, Gene expression of the 7 isoforms of SGLT Transporters was evaluated in vascular tissues by PCR. Then, in order to study the involvement of SGLT/SMIT transporters in HG-related vascular alterations, we incubated (1 hour, 100 mM) aortic rings from Wistar rats with either of the following sugars which each stimulate either one or more isoforms of these transporters (Glucose: GLUTs/SGLTs/SMITs transporters; α-MG: SGLT 1 to 5; Galactose: SGLT 1/2; myo-inositol: SMIT 1/2; L-Fucose: SMIT1). Then, incubated vessels were either mounted in organ chambers to study vascular endothelial function or embedded in OCT in order to measure reactive oxygen species (ROS) production with DHE fluorescence. First, PCR analyses highlighted that SMIT1 appears to be the transporter of the SGLT family whose gene expression is predominant in vascular tissue. As expected from previous studies, vascular exposure to glucose was responsible for an endothelial dysfunction associated with a higher ROS production. Interestingly, endothelial impairments and increased ROS production were not observed when SGLTs were stimulated with either α-MG or galactose. The main result of this work was that myo-inositol exposure was responsible for similar endothelial alteration than glucose and that L-Fucose which transport is highly dependent of SMIT1 was responsible for an exacerbation of those impairments. These results highlight the implication of SMIT1 in the increased oxidative stress and endothelial dysfunctions observed during HG in vascular tissues.