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 journalArticle

5 Citations (Scopus)

Abstract

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
Volume11
Issue number5
StatePublished - Jan 1 2014

Fingerprint

Arginase
Nitric Oxide
Transcription Factors
Up-Regulation
Glucose
Blood Vessels
Endothelial cells
Endothelial Cells
Medical problems
Luciferases
Diabetes Mellitus
Activating Transcription Factors
Nitric Oxide Synthase Type III
Vascular Diseases
Nitric Oxide Synthase
Small Interfering RNA
Transfection
Arginine
Cardiovascular Diseases
Genes

Keywords

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

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

High glucose upregulates arginase 1 and decreases nitric oxide production through ATF-2 and c-Jun transcription factors. / Shatanawi, Alia; Gharaibeh, Munir N.; Caldwell, Ruth B.; Caldwell, R. William.

In: Life Science Journal, Vol. 11, No. 5, 50, 01.01.2014, p. 374-379.

Research output: Contribution to journalArticle

@article{58b4a815b7bf4ca78e3abd1e435b7f9c,
title = "High glucose upregulates arginase 1 and decreases nitric oxide production through ATF-2 and c-Jun transcription factors",
abstract = "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.",
keywords = "ATF-2, Arginase, C-jun, Diabetes, High glucose, Nitric oxide, Transcription factors",
author = "Alia Shatanawi and Gharaibeh, {Munir N.} and Caldwell, {Ruth B.} and Caldwell, {R. William}",
year = "2014",
month = "1",
day = "1",
language = "English (US)",
volume = "11",
pages = "374--379",
journal = "Life Science Journal",
issn = "1097-8135",
publisher = "Zhengzhou University",
number = "5",

}

TY - JOUR

T1 - High glucose upregulates arginase 1 and decreases nitric oxide production through ATF-2 and c-Jun transcription factors

AU - Shatanawi, Alia

AU - Gharaibeh, Munir N.

AU - Caldwell, Ruth B.

AU - Caldwell, R. William

PY - 2014/1/1

Y1 - 2014/1/1

N2 - 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.

AB - 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.

KW - ATF-2

KW - Arginase

KW - C-jun

KW - Diabetes

KW - High glucose

KW - Nitric oxide

KW - Transcription factors

UR - http://www.scopus.com/inward/record.url?scp=84899138507&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84899138507&partnerID=8YFLogxK

M3 - Article

AN - SCOPUS:84899138507

VL - 11

SP - 374

EP - 379

JO - Life Science Journal

JF - Life Science Journal

SN - 1097-8135

IS - 5

M1 - 50

ER -