Cyclosporine attenuates arginine transport, in human endothelial cells, through modulation of cationic amino acid transporter-1

Ayelet Grupper, Moshe Shashar, Dganit Bahry, Yael Pri-Paz, Ohad Ben Tur, Sharon Levi, Tamara Chernichovski, Gil Chernin, Idit F. Schwartz

Research output: Contribution to journalArticlepeer-review

Abstract

Background: The spectrum of cardiovascular toxicity by cyclosporine (CsA) includes hypertension, accelerated atherosclerosis, and thrombotic microangiopathy, all of which are the result of endothelial cell dysfunction. Endothelial cell dysfunction is characterized by decreased endothelial nitric oxide synthase (eNOS) activity. Cationic amino acid transporter-1 (CAT-1) is the specific arginine transporter for eNOS. CsA has been shown to attenuate nitric oxide (NO) generation. However, the mechanism remains elusive. We hypothesize that CsA inhibits eNOS activity through modulation of its selective arginine supplier CAT-1. Methods: We studied the effect of CsA on arginine uptake, NO2/NO3 generation, and CAT-1, protein kinase C (PKC), and phosphorylated PKC protein expression in human umbilical vein endothelial cell cultures (HUVEC) in the absence and presence of L-arginine. Results: CsA (0.5-2 μg/ml) significantly attenuated arginine transport in a dose- and time-dependent manner, a phenomenon which was prevented by co-incubation with L-arginine (1 mM). The aforementioned findings were accompanied by increased protein nitration, a measure for peroxynitrite accumulation. In contrast, no changes were observed in NO2/NO3 generation. CsA significantly decreased the abundance of CAT-1 protein, an effect that was attenuated by L-arginine. PKC and phosphorylated PKC (CAT-1 inhibitors) protein contents were not affected by CsA. Conclusion: CsA inhibits arginine transport and induces protein nitration in HUVEC through modulation of CAT-1.

Original languageEnglish
Pages (from-to)613-619
Number of pages7
JournalAmerican Journal of Nephrology
Volume37
Issue number6
DOIs
StatePublished - 2013
Externally publishedYes

Keywords

  • Endothelial dysfunction
  • L-Arginine
  • Nitric oxide

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