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.; ClintonWebb, R.; Caldwell, Ruth B.; Caldwell, R. William

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 2weeks of DOCA-salt treatment, systolic blood pressure (SBP) was increased by s15mmHg in all mouse genotypes. SBP continued to rise in DOCA-saltWT and ARG2-/- mice to s130mmHg at 5-6weeks, whereas in ARG1 /- mice SBP waned toward control levels by 6weeks (109±4 vs. 101±3mmHg, 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 fromWT-DOCA mice with arginase inhibitor (100mM) improved endotheliummediated vasorelaxation. DOCA-salt-induced coronary perivascular fibrosis (increased by 2.1-fold) inWTwas 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.

ARGINASE; BLOOD pressure; ENDOTHELIAL cells; LABORATORY mice; HYPERTENSION; ANTIHYPERTENSIVE agents

Frontiers in Immunology, 2013, Vol 4, p1

1664-3224

Academic Journal

10.3389/fimmu.2013.00219