title: Angiotensin II limits NO production by upregulating arginase through a p38 MAPK-ATF-2 pathway.
abstract: 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.
authors.affiliation: Department of Pharmacology, Faculty of Medicine, The University of Jordan, Amman 11942, Jordan; Department of Pharmacology and Toxicology, Medical College of Georgia, Georgia Regents University, Augusta, GA 30912, USA. Electronic address: a.shatanawi@ju.edu.jo.
authors.forename: Alia
authors.initials: A
authors.lastname: Shatanawi
authors.affiliation: Vascular Biology Center, Medical College of Georgia, Georgia Regents University, Augusta, GA 30912, USA.
authors.forename: Tahira
authors.initials: T
authors.lastname: Lemtalsi
authors.affiliation: Department of Pharmacology and Toxicology, Medical College of Georgia, Georgia Regents University, Augusta, GA 30912, USA.
authors.forename: Lin
authors.initials: L
authors.lastname: Yao
authors.affiliation: Vascular Biology Center, Medical College of Georgia, Georgia Regents University, Augusta, GA 30912, USA.
authors.forename: Chintan
authors.initials: C
authors.lastname: Patel
authors.affiliation: Vascular Biology Center, Medical College of Georgia, Georgia Regents University, Augusta, GA 30912, USA; VA Medical Center, Augusta, GA 30912, USA.
authors.forename: Ruth B
authors.initials: RB
authors.lastname: Caldwell
authors.affiliation: Department of Pharmacology and Toxicology, Medical College of Georgia, Georgia Regents University, Augusta, GA 30912, USA.
authors.forename: R William
authors.initials: RW
authors.lastname: Caldwell
mesh_terms: D051698:Activating Transcription Factor 2 / Q000378:metabolism*; D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D001011:Aorta / Q000166:cytology; D001119:Arginase / Q000235:genetics*; D001665:Binding Sites; D002417:Cattle; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008156:Luciferases / Q000235:genetics; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D009569:Nitric Oxide / Q000096:biosynthesis*; D010766:Phosphorylation / Q000187:drug effects; D011401:Promoter Regions, Genetic / Q000235:genetics; D018808:Transcription Factor AP-1 / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects; D015854:Up-Regulation / Q000187:drug effects*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: D051698:Activating Transcription Factor 2; D018808:Transcription Factor AP-1; D000804:Angiotensin II; D009569:Nitric Oxide; D008156:Luciferases; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D001119:Arginase
keywords: ATF-2; Angiotensin II; Arginase; Nitric oxide (NO); Transcription factors; p38 MAPK