A role for insulin on L-arginine transport in fetal endothelial dysfunction in hyperglycaemia

Curr Vasc Pharmacol. 2009 Oct;7(4):467-74. doi: 10.2174/157016109789043919.


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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Arginine / metabolism*
  • Biological Transport
  • Cationic Amino Acid Transporter 1 / biosynthesis
  • Cationic Amino Acid Transporter 1 / genetics
  • Endothelium, Vascular / metabolism*
  • Endothelium, Vascular / physiopathology
  • Fetus / blood supply*
  • Glucose / pharmacology
  • Humans
  • Hyperglycemia / metabolism*
  • Hyperglycemia / physiopathology
  • Insulin / pharmacology*
  • Insulin / physiology
  • NF-kappa B / metabolism
  • Nitric Oxide Synthase Type III / metabolism
  • Reactive Oxygen Species / metabolism
  • Umbilical Veins / drug effects
  • Umbilical Veins / metabolism


  • Cationic Amino Acid Transporter 1
  • Insulin
  • NF-kappa B
  • Reactive Oxygen Species
  • SLC7A1 protein, human
  • Arginine
  • Nitric Oxide Synthase Type III
  • Glucose