High glucose upregulates arginase 1 and decreases nitric oxide production through ATF-2 and c-Jun transcription factors

Alia Shatanawi, Munir N. Gharaibeh, Ruth B. Caldwell, R. William Caldwell

Research output: Contribution to journalArticlepeer-review

5 Scopus citations


Diabetes mellitus is a major risk factor for the development of cardiovascular diseases. Vascular endothelial dysfunction (VED) is a major contributor to the pathogenesis of vascular disease in diabetes mellitus. VED is characterized by impaired endothelial cell (EC) production or availability of nitric oxide (NO). NO produced by endothelial NO synthase (eNOS) is needed for normal vascular function. VED of diabetes has been linked to elevated levels of arginase which can compete with eNOS for available L-arginine. This will reduce vascular NO production. In this study, transcriptional regulation of arginase was explored in response to high glucose (HG) in EC. Treatment of EC with HG (25 mM, 72 hrs) caused a 55.3±3.1% increase in arginase activity accompanied by a 32.4±5.9% decrease in NO production. The involvement of two transcription factors of the AP1 family; ATF- 2 and c-Jun was studied. Depletion of ATF-2 or c-Jun by siRNAs prevented both of the effects of HG on arginase activity and NO production. In addition, HG enhanced arginase 1 gene transcriptional activity (1.6 folds, p<0.05) measured as luciferase activity in ECs transfected with arginase 1 promotor luciferase. Transfection of EC with ATF-2 or c- Jun siRNA prevented the enhancement of luciferase activity. This indicates that ATF-2 and c-Jun are necessary for enhanced expression of arginase 1 under HG conditions. The data indicate that HG limits NO production while upregulating arginase 1 expression via transcription factors ATF-2 and c-Jun. These signaling steps might be therapeutic targets for preventing VED associated with elevated arginase levels.

Original languageEnglish (US)
Article number50
Pages (from-to)374-379
Number of pages6
JournalLife Science Journal
Issue number5
StatePublished - Jan 1 2014


  • ATF-2
  • Arginase
  • C-jun
  • Diabetes
  • High glucose
  • Nitric oxide
  • Transcription factors

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)


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