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 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.
authors.affiliation: Department of Pharmacology and Toxicology, Georgia Regents University , Augusta, GA , USA.
authors.forename: Haroldo A
authors.initials: HA
authors.lastname: Toque
authors.forename: Kenia P
authors.initials: KP
authors.lastname: Nunes
authors.forename: Modesto
authors.initials: M
authors.lastname: Rojas
authors.forename: Anil
authors.initials: A
authors.lastname: Bhatta
authors.forename: Lin
authors.initials: L
authors.lastname: Yao
authors.forename: Zhimin
authors.initials: Z
authors.lastname: Xu
authors.forename: Maritza J
authors.initials: MJ
authors.lastname: Romero
authors.forename: R Clinton
authors.initials: RC
authors.lastname: Webb
authors.forename: Ruth B
authors.initials: RB
authors.lastname: Caldwell
authors.forename: R William
authors.initials: RW
authors.lastname: Caldwell
keywords: DOCA-salt; arginase; endothelial dysfunction; fibrosis; hypertension
references.citation: Hypertension. 2004 Dec;44(6):935-43
references.pmid: 15492130
references.citation: J Hypertens. 2005 May;23(5):971-8
references.pmid: 15834282
references.citation: Hypertension. 1986 Jun;8(6 Pt 2):II127-34
references.pmid: 3522418
references.citation: J Sex Med. 2010 Dec;7(12):3857-67
references.pmid: 20807329
references.citation: Circulation. 2000 Apr 11;101(14):1722-8
references.pmid: 10758056
references.citation: J Mol Cell Cardiol. 2004 Nov;37(5):939-45
references.pmid: 15522271
references.citation: Am J Physiol Cell Physiol. 2011 May;300(5):C1181-92
references.pmid: 21289285
references.citation: Cardiol Res Pract. 2011;2011:263585
references.pmid: 21845218
references.citation: Cardiovasc Res. 2010 Aug 1;87(3):569-77
references.pmid: 20219858
references.citation: Circ Res. 2008 Jan 4;102(1):95-102
references.pmid: 17967788
references.citation: Circulation. 2003 Oct 21;108(16):2000-6
references.pmid: 14517171
references.citation: Circulation. 2004 Dec 14;110(24):3708-14
references.pmid: 15569838
references.citation: Cardiovasc Res. 2010 Jan 1;85(1):194-203
references.pmid: 19684035
references.citation: Am J Physiol Endocrinol Metab. 2001 Jan;280(1):E75-82
references.pmid: 11120661
references.citation: FASEB J. 2004 Nov;18(14):1746-8
references.pmid: 15364894
references.citation: Curr Hypertens Rep. 2009 Dec;11(6):444-9
references.pmid: 19895756
references.citation: Mol Cell Biol. 2002 Jul;22(13):4491-8
references.pmid: 12052859
references.citation: Hypertension. 2009 Aug;54(2):294-301
references.pmid: 19546381
references.citation: Hypertension. 2007 Dec;50(6):1057-62
references.pmid: 17923589
references.citation: Hypertension. 2001 Nov;38(5):1107-11
references.pmid: 11711506
references.citation: Circ Res. 2008 Apr 25;102(8):923-32
references.pmid: 18309100
references.citation: J Sex Med. 2011 Mar;8(3):722-33
references.pmid: 21054801
references.citation: Eur J Pharmacol. 2008 Jan 28;579(1-3):403-10
references.pmid: 18001708
references.citation: Am J Pathol. 2009 Aug;175(2):891-902
references.pmid: 19590038
references.citation: Hypertension. 1996 Dec;28(6):1064-9
references.pmid: 8952597
references.citation: Clin Exp Hypertens. 2000 Jan;22(1):75-85
references.pmid: 10685726
references.citation: Br J Pharmacol. 2009 Jul;157(6):922-30
references.pmid: 19508396
references.citation: Am J Physiol Regul Integr Comp Physiol. 2005 Apr;288(4):R1057-62
references.pmid: 15591155
references.citation: Clin Exp Pharmacol Physiol. 2007 Sep;34(9):906-11
references.pmid: 17645639
references.citation: FASEB J. 2003 Dec;17(15):2328-30
references.pmid: 14563685
references.citation: Nephrol Dial Transplant. 2003 Oct;18(10):1999-2004
references.pmid: 13679473
references.citation: Comp Biochem Physiol B Biochem Mol Biol. 1996 May;114(1):107-32
references.pmid: 8759304
references.citation: Br J Pharmacol. 2012 Jan;165(2):506-19
references.pmid: 21740411
references.citation: Life Sci. 2007 Feb 27;80(12):1128-34
references.pmid: 17223136
references.citation: Annu Rev Nutr. 2002;22:87-105
references.pmid: 12055339
references.citation: Circulation. 2001 Feb 27;103(8):1121-7
references.pmid: 11222476