Cargando…

Arginase 1 Mediates Increased Blood Pressure and Contributes to Vascular Endothelial Dysfunction in Deoxycorticosterone Acetate-Salt Hypertension

Enhanced arginase (ARG) activity has been identified as a factor that reduces nitric oxide production and impairs endothelial function in vascular pathologies. Using a gene deletion model, we investigated involvement of arginase isoforms arginase 1 and 2 (ARG1 and ARG2) in hypertension and endotheli...

Descripción completa

Detalles Bibliográficos
Autores principales: Toque, Haroldo A., Nunes, Kenia P., Rojas, Modesto, Bhatta, Anil, Yao, Lin, Xu, Zhimin, Romero, Maritza J., Webb, R. Clinton, Caldwell, Ruth B., Caldwell, R. William
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2013
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3725429/
https://www.ncbi.nlm.nih.gov/pubmed/23908657
http://dx.doi.org/10.3389/fimmu.2013.00219
_version_ 1782476790342615040
author Toque, Haroldo A.
Nunes, Kenia P.
Rojas, Modesto
Bhatta, Anil
Yao, Lin
Xu, Zhimin
Romero, Maritza J.
Webb, R. Clinton
Caldwell, Ruth B.
Caldwell, R. William
author_facet Toque, Haroldo A.
Nunes, Kenia P.
Rojas, Modesto
Bhatta, Anil
Yao, Lin
Xu, Zhimin
Romero, Maritza J.
Webb, R. Clinton
Caldwell, Ruth B.
Caldwell, R. William
author_sort Toque, Haroldo A.
collection PubMed
description Enhanced arginase (ARG) activity has been identified as a factor that reduces nitric oxide production and impairs endothelial function in vascular pathologies. Using a gene deletion model, we investigated involvement of arginase isoforms arginase 1 and 2 (ARG1 and ARG2) in hypertension and endothelial dysfunction in a mineralocorticoid-salt mouse model. Hypertension was induced in wild type (WT), partial ARG1(+/−) knockout (KO), and complete ARG2(−/−) KO mice by uninephrectomy and deoxycorticosterone acetate (DOCA)-salt treatment for 6-weeks. (Control uninephrectomized mice drank tap water.) After 2 weeks of DOCA-salt treatment, systolic blood pressure (SBP) was increased by ∼15 mmHg in all mouse genotypes. SBP continued to rise in DOCA-salt WT and ARG2(−/−) mice to ∼130 mmHg at 5–6 weeks, whereas in ARG1(+/−) mice SBP waned toward control levels by 6 weeks (109 ± 4 vs. 101 ± 3 mmHg, respectively). DOCA-salt treatment in WT mice increased vascular ARG activity (aorta by 1.5-fold; mesenteric artery (MA) by 2.6-fold and protein levels of ARG1 (aorta: 1.49-fold and MA: 1.73-fold) vs. WT Sham tissues. ARG2 protein increased in WT-DOCA MA (by 2.15-fold) but not in aorta compared to those of WT Sham tissues. Maximum endothelium-dependent vasorelaxation to acetylcholine was significantly reduced in DOCA-salt WT mice and largely or partially maintained in DOCA ARG1(+/−) and ARG2(−/−) mice vs. their Sham controls. DOCA-salt augmented contractile responses to phenylephrine in aorta of all mouse genotypes. Additionally, treatment of aorta or MA from WT-DOCA mice with arginase inhibitor (100 μM) improved endothelium-mediated vasorelaxation. DOCA-salt-induced coronary perivascular fibrosis (increased by 2.1-fold) in WT was prevented in ARG1(+/−) and reduced in ARG2(−/−) mice. In summary, ARG is involved in murine DOCA-salt-induced impairment of vascular function and hypertension and may represent a novel target for antihypertensive therapy.
format Online
Article
Text
id pubmed-3725429
institution National Center for Biotechnology Information
language English
publishDate 2013
publisher Frontiers Media S.A.
record_format MEDLINE/PubMed
spelling pubmed-37254292013-08-01 Arginase 1 Mediates Increased Blood Pressure and Contributes to Vascular Endothelial Dysfunction in Deoxycorticosterone Acetate-Salt Hypertension Toque, Haroldo A. Nunes, Kenia P. Rojas, Modesto Bhatta, Anil Yao, Lin Xu, Zhimin Romero, Maritza J. Webb, R. Clinton Caldwell, Ruth B. Caldwell, R. William Front Immunol Immunology Enhanced arginase (ARG) activity has been identified as a factor that reduces nitric oxide production and impairs endothelial function in vascular pathologies. Using a gene deletion model, we investigated involvement of arginase isoforms arginase 1 and 2 (ARG1 and ARG2) in hypertension and endothelial dysfunction in a mineralocorticoid-salt mouse model. Hypertension was induced in wild type (WT), partial ARG1(+/−) knockout (KO), and complete ARG2(−/−) KO mice by uninephrectomy and deoxycorticosterone acetate (DOCA)-salt treatment for 6-weeks. (Control uninephrectomized mice drank tap water.) After 2 weeks of DOCA-salt treatment, systolic blood pressure (SBP) was increased by ∼15 mmHg in all mouse genotypes. SBP continued to rise in DOCA-salt WT and ARG2(−/−) mice to ∼130 mmHg at 5–6 weeks, whereas in ARG1(+/−) mice SBP waned toward control levels by 6 weeks (109 ± 4 vs. 101 ± 3 mmHg, respectively). DOCA-salt treatment in WT mice increased vascular ARG activity (aorta by 1.5-fold; mesenteric artery (MA) by 2.6-fold and protein levels of ARG1 (aorta: 1.49-fold and MA: 1.73-fold) vs. WT Sham tissues. ARG2 protein increased in WT-DOCA MA (by 2.15-fold) but not in aorta compared to those of WT Sham tissues. Maximum endothelium-dependent vasorelaxation to acetylcholine was significantly reduced in DOCA-salt WT mice and largely or partially maintained in DOCA ARG1(+/−) and ARG2(−/−) mice vs. their Sham controls. DOCA-salt augmented contractile responses to phenylephrine in aorta of all mouse genotypes. Additionally, treatment of aorta or MA from WT-DOCA mice with arginase inhibitor (100 μM) improved endothelium-mediated vasorelaxation. DOCA-salt-induced coronary perivascular fibrosis (increased by 2.1-fold) in WT was prevented in ARG1(+/−) and reduced in ARG2(−/−) mice. In summary, ARG is involved in murine DOCA-salt-induced impairment of vascular function and hypertension and may represent a novel target for antihypertensive therapy. Frontiers Media S.A. 2013-07-29 /pmc/articles/PMC3725429/ /pubmed/23908657 http://dx.doi.org/10.3389/fimmu.2013.00219 Text en Copyright © 2013 Toque, Nunes, Rojas, Bhatta, Yao, Xu, Romero, Webb, Caldwell and Caldwell. http://creativecommons.org/licenses/by/3.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in other forums, provided the original authors and source are credited and subject to any copyright notices concerning any third-party graphics etc.
spellingShingle Immunology
Toque, Haroldo A.
Nunes, Kenia P.
Rojas, Modesto
Bhatta, Anil
Yao, Lin
Xu, Zhimin
Romero, Maritza J.
Webb, R. Clinton
Caldwell, Ruth B.
Caldwell, R. William
Arginase 1 Mediates Increased Blood Pressure and Contributes to Vascular Endothelial Dysfunction in Deoxycorticosterone Acetate-Salt Hypertension
title Arginase 1 Mediates Increased Blood Pressure and Contributes to Vascular Endothelial Dysfunction in Deoxycorticosterone Acetate-Salt Hypertension
title_full Arginase 1 Mediates Increased Blood Pressure and Contributes to Vascular Endothelial Dysfunction in Deoxycorticosterone Acetate-Salt Hypertension
title_fullStr Arginase 1 Mediates Increased Blood Pressure and Contributes to Vascular Endothelial Dysfunction in Deoxycorticosterone Acetate-Salt Hypertension
title_full_unstemmed Arginase 1 Mediates Increased Blood Pressure and Contributes to Vascular Endothelial Dysfunction in Deoxycorticosterone Acetate-Salt Hypertension
title_short Arginase 1 Mediates Increased Blood Pressure and Contributes to Vascular Endothelial Dysfunction in Deoxycorticosterone Acetate-Salt Hypertension
title_sort arginase 1 mediates increased blood pressure and contributes to vascular endothelial dysfunction in deoxycorticosterone acetate-salt hypertension
topic Immunology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3725429/
https://www.ncbi.nlm.nih.gov/pubmed/23908657
http://dx.doi.org/10.3389/fimmu.2013.00219
work_keys_str_mv AT toqueharoldoa arginase1mediatesincreasedbloodpressureandcontributestovascularendothelialdysfunctionindeoxycorticosteroneacetatesalthypertension
AT nuneskeniap arginase1mediatesincreasedbloodpressureandcontributestovascularendothelialdysfunctionindeoxycorticosteroneacetatesalthypertension
AT rojasmodesto arginase1mediatesincreasedbloodpressureandcontributestovascularendothelialdysfunctionindeoxycorticosteroneacetatesalthypertension
AT bhattaanil arginase1mediatesincreasedbloodpressureandcontributestovascularendothelialdysfunctionindeoxycorticosteroneacetatesalthypertension
AT yaolin arginase1mediatesincreasedbloodpressureandcontributestovascularendothelialdysfunctionindeoxycorticosteroneacetatesalthypertension
AT xuzhimin arginase1mediatesincreasedbloodpressureandcontributestovascularendothelialdysfunctionindeoxycorticosteroneacetatesalthypertension
AT romeromaritzaj arginase1mediatesincreasedbloodpressureandcontributestovascularendothelialdysfunctionindeoxycorticosteroneacetatesalthypertension
AT webbrclinton arginase1mediatesincreasedbloodpressureandcontributestovascularendothelialdysfunctionindeoxycorticosteroneacetatesalthypertension
AT caldwellruthb arginase1mediatesincreasedbloodpressureandcontributestovascularendothelialdysfunctionindeoxycorticosteroneacetatesalthypertension
AT caldwellrwilliam arginase1mediatesincreasedbloodpressureandcontributestovascularendothelialdysfunctionindeoxycorticosteroneacetatesalthypertension