A role for insulin on L-arginine transport in fetal endothelial dysfunction in hyperglycaemia.
Endothelial cells are key in the regulation of vascular tone through the release of vasoactive molecules, including nitric oxide (NO). NO is a gas synthesized from the cationic amino acid L-arginine via the endothelial NO synthase (eNOS). The semi-essential amino acid L-arginine is a taken up by endothelial cells via systems y(+) and y(+)L in primary cultures of human umbilical vein endothelial cells (HUVEC). System y(+) is a family of membrane transporters including at least five transport systems for cationic amino acids (CAT) of which HUVEC express human CAT-1 (hCAT-1) and hCAT-2B. Exposure of HUVEC to high extracellular concentrations of D-glucose increases L-arginine transport, hCAT-1 mRNA expression and eNOS activity. These phenomena are also related with increased production of reactive oxygen species (ROS), thus supporting the possibility that changes in L-arginine/NO signalling pathway result from elevated ROS. It has been shown that insulin blocks D-glucose-increased L-arginine transport and cGMP accumulation in HUVEC, whereas in this cell type insulin also modulates high D-glucose effects by activating the transcriptional factors Sp1 and NFkappaB. These transcription factors have response elements in SLC7A1 (for hCAT-1) gene promoter region, thus representing 2 possible targets for regulation of the expression of this transporter by D-glucose and/or insulin in this cell type. Recent evidences suggest that insulin blocks the stimulatory effect of D-glucose on L-arginine transport by reducing the transcriptional activity of SLC7A1 via Sp1-, NFkappaB- and ROS-dependent mechanisms. Thus, a role for these transcription factors in response to insulin is proposed in fetal endothelial cells exposed to hyperglycaemia.
Sobrevia
Luis
L
Cellular and Molecular Physiology Laboratory, Department of Obstetrics and Gynaecology, Medical Research Centre, School of Medicine, Pontificia Universidad Católica de Chile. P.O. Box 114-D, Santiago, Chile. sobrevia@med.puc.cl
González
Marcelo
M
D001120:Arginine / Q000378:metabolism*; D001692:Biological Transport; D027201:Cationic Amino Acid Transporter 1 / Q000096:biosynthesis / Q000235:genetics; D004730:Endothelium, Vascular / Q000378:metabolism* / Q000503:physiopathology; D005333:Fetus / Q000098:blood supply*; D005947:Glucose / Q000494:pharmacology; D006801:Humans; D006943:Hyperglycemia / Q000378:metabolism* / Q000503:physiopathology; D007328:Insulin / Q000494:pharmacology* / Q000502:physiology; D016328:NF-kappa B / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D014471:Umbilical Veins / Q000187:drug effects / Q000378:metabolism
D027201:Cationic Amino Acid Transporter 1; D007328:Insulin; D016328:NF-kappa B; D017382:Reactive Oxygen Species; C420825:SLC7A1 protein, human; D001120:Arginine; D052250:Nitric Oxide Synthase Type III; D005947:Glucose