Angiotensin II limits NO production by upregulating arginase through a p38 MAPK-ATF-2 pathway

Alia Shatanawi, Tahira Lemtalsi, Lin Yao, Chintan Patel, Ruth B. Caldwell, R. William Caldwell

Research output: Contribution to journalArticlepeer-review

35 Scopus citations


Enhanced vascular arginase activity can impair endothelium-dependent vasorelaxation by decreasing l-arginine availability to endothelial nitric oxide (NO) synthase, thereby reducing NO production and uncoupling NOS function. Elevated angiotensin II (Ang II) is a key component of endothelial dysfunction in many cardiovascular diseases and has been linked to elevated arginase activity. In this study we explored the signaling pathway leading to increased arginase expression/activity in response to Ang II in bovine aortic endothelial cells (BAEC). Our previous studies indicate involvement of p38 mitogen activated protein kinase (MAPK) in Ang II-induced arginase upregulation and reduced NO production. In this study, we further investigated the Ang II-transcriptional regulation of arginase 1 in endothelial cells. Our results indicate the involvement of ATF-2 transcription factor of the AP1 family in arginase 1 upregulation and in limiting NO production. Using small interfering RNA (siRNA) targeting ATF-2, we showed that this transcription factor is required for Ang II-induced arginase 1 gene upregulation and increased arginase 1 expression and activity, leading to reduced NO production. Electrophoretic mobility shift assay and chromatin immunoprecipitation assay further confirmed the involvement of ATF-2. Moreover, our data indicate that p38 MAPK phosphorylates ATF-2 in response to Ang II. Collectively, our results indicate that Ang II increases endothelial arginase activity/expression through a p38 MAPK/ATF-2 pathway leading to reduced endothelial NO production. These signaling steps might be therapeutic targets for preventing vascular endothelial dysfunction associated with elevated arginase activity/expression.

Original languageEnglish (US)
Pages (from-to)106-114
Number of pages9
JournalEuropean Journal of Pharmacology
StatePublished - Jan 5 2015


  • ATF-2
  • Angiotensin II
  • Arginase
  • Nitric oxide (NO)
  • Transcription factors
  • p38 MAPK

ASJC Scopus subject areas

  • Pharmacology


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