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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 106-114 |
| Number of pages | 9 |
| Journal | European Journal of Pharmacology |
| Volume | 746 |
| DOIs | |
| State | Published - Jan 5 2015 |
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Keywords
- ATF-2
- Angiotensin II
- Arginase
- Nitric oxide (NO)
- Transcription factors
- p38 MAPK
ASJC Scopus subject areas
- Pharmacology
Cite this
Angiotensin II limits NO production by upregulating arginase through a p38 MAPK-ATF-2 pathway. / Shatanawi, Alia; Lemtalsi, Tahira; Yao, Lin; Patel, Chintan; Caldwell, Ruth B; Caldwell, Robert William.
In: European Journal of Pharmacology, Vol. 746, 05.01.2015, p. 106-114.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Angiotensin II limits NO production by upregulating arginase through a p38 MAPK-ATF-2 pathway
AU - Shatanawi, Alia
AU - Lemtalsi, Tahira
AU - Yao, Lin
AU - Patel, Chintan
AU - Caldwell, Ruth B
AU - Caldwell, Robert William
PY - 2015/1/5
Y1 - 2015/1/5
N2 - 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.
AB - 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.
KW - ATF-2
KW - Angiotensin II
KW - Arginase
KW - Nitric oxide (NO)
KW - Transcription factors
KW - p38 MAPK
UR - http://www.scopus.com/inward/record.url?scp=84949116884&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84949116884&partnerID=8YFLogxK
U2 - 10.1016/j.ejphar.2014.10.042
DO - 10.1016/j.ejphar.2014.10.042
M3 - Article
VL - 746
SP - 106
EP - 114
JO - European Journal of Pharmacology
JF - European Journal of Pharmacology
SN - 0014-2999
ER -