Arginase 1 mediates increased blood pressure and contributes to vascular endothelial dysfunction in deoxycorticosterone acetate-salt hypertension

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Abstract

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-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 ~M) improved endothelium-mediated vasorelaxation. DOCA-saltinduced 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.

Original languageEnglish (US)
Article numberArticle 219
JournalFrontiers in Immunology
Volume4
Issue numberJUL
DOIs
StatePublished - Sep 16 2013

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Arginase
Desoxycorticosterone
Blood Vessels
Acetates
Salts
Blood Pressure
Hypertension
Mesenteric Arteries
Aorta
Vasodilation
Endothelium
Genotype
Mineralocorticoids
Gene Deletion
Phenylephrine
Knockout Mice
Antihypertensive Agents
Acetylcholine
Nitric Oxide
Protein Isoforms

Keywords

  • Arginase
  • DOCA-salt
  • Endothelial dysfunction
  • Fibrosis
  • Hypertension

ASJC Scopus subject areas

  • Immunology
  • Immunology and Allergy

Cite this

@article{9a548d4debd743fdbb33004fbf0bf759,
title = "Arginase 1 mediates increased blood pressure and contributes to vascular endothelial dysfunction in deoxycorticosterone acetate-salt hypertension",
abstract = "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-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 ~M) improved endothelium-mediated vasorelaxation. DOCA-saltinduced 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.",
keywords = "Arginase, DOCA-salt, Endothelial dysfunction, Fibrosis, Hypertension",
author = "{Flores Toque}, {Haroldo Alfredo} and Nunes, {Kenia P.} and Rojas, {Modesto Antonio} and Anil Bhatta and Lin Yao and Zhimin Xu and {Romero Lucas}, {Maritza Josefina} and Webb, {R Clinton} and Caldwell, {Ruth B} and Caldwell, {Robert William}",
year = "2013",
month = "9",
day = "16",
doi = "10.3389/fimmu.2013.00219",
language = "English (US)",
volume = "4",
journal = "Frontiers in Immunology",
issn = "1664-3224",
publisher = "Frontiers Media S. A.",
number = "JUL",

}

TY - JOUR

T1 - Arginase 1 mediates increased blood pressure and contributes to vascular endothelial dysfunction in deoxycorticosterone acetate-salt hypertension

AU - Flores Toque, Haroldo Alfredo

AU - Nunes, Kenia P.

AU - Rojas, Modesto Antonio

AU - Bhatta, Anil

AU - Yao, Lin

AU - Xu, Zhimin

AU - Romero Lucas, Maritza Josefina

AU - Webb, R Clinton

AU - Caldwell, Ruth B

AU - Caldwell, Robert William

PY - 2013/9/16

Y1 - 2013/9/16

N2 - 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-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 ~M) improved endothelium-mediated vasorelaxation. DOCA-saltinduced 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.

AB - 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-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 ~M) improved endothelium-mediated vasorelaxation. DOCA-saltinduced 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.

KW - Arginase

KW - DOCA-salt

KW - Endothelial dysfunction

KW - Fibrosis

KW - Hypertension

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U2 - 10.3389/fimmu.2013.00219

DO - 10.3389/fimmu.2013.00219

M3 - Article

C2 - 23908657

AN - SCOPUS:84883690434

VL - 4

JO - Frontiers in Immunology

JF - Frontiers in Immunology

SN - 1664-3224

IS - JUL

M1 - Article 219

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