Regulation of arginine transport and metabolism by Protein Kinase Cα in endothelial cells: Stimulation of CAT2 transporters and arginase activity

Rossana Visigalli, Amelia Barilli, Alessandro Parolari, Roberto Sala, Bianca Maria Rotoli, Ovidio Bussolati, Gian C. Gazzola, Valeria Dall'Asta

Research output: Contribution to journalArticle

Abstract

Endothelial metabolism of arginine plays a key role in vascular homeostasis. While it is documented that the availability of extracellular arginine is critical for nitric oxide synthesis by eNOS, little is known about the relationships existing between arginine transport and the activity of arginase, the enzyme responsible for the production of ornithine and urea. The present study aims to characterize the role of PKC in the regulation of arginine transport and metabolism by human umbilical vein (HUVEC) and aortic (HAEC) endothelial cells. The results obtained demonstrate that the activation of PKCα by phorbol esters or thymeleatoxin causes a transient increase of arginine transport through system y+, referable to the induction of SLC7A2 mRNAs and to the increased expression of CAT2 transporters. PKCα-dependent stimulation of arginine transport requires the activation of MEK/ERK1/2 cascade, which leads to the stimulation of AP-1 and to the consequent induction of CAT2 expression. In parallel, PKCα activation also increases arginase expression and activity and promotes eNOS phosphorylation, resulting in decreased NO production. It is concluded that the activation of PKCα stimulates arginine entry in human endothelial cells and shifts the metabolism of the cationic amino acid from NO synthesis to arginase-dependent production of ornithine and urea. This metabolic deviation may contribute to the endothelial dysfunction associated with conditions of PKC overactivity.

Original languageEnglish
Pages (from-to)260-270
Number of pages11
JournalJournal of Molecular and Cellular Cardiology
Volume49
Issue number2
DOIs
Publication statusPublished - Aug 2010

Keywords

  • AP-1
  • Arginase
  • Arginine transport
  • Cationic Amino Acid Transporters
  • Endothelial dysfunction
  • Endothelium
  • ERK
  • Nitric oxide
  • Protein Kinase C
  • SLC7A genes

ASJC Scopus subject areas

  • Molecular Biology
  • Cardiology and Cardiovascular Medicine

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