AUTHOR=Toque Haroldo A., Nunes Kenia P., Rojas Modesto , Bhatta Anil , Yao Lin , Xu Zhimin , Romero Maritza J., Webb R. C., Caldwell Ruth B., Caldwell R. W. TITLE=Arginase 1 Mediates Increased Blood Pressure and Contributes to Vascular Endothelial Dysfunction in Deoxycorticosterone Acetate-Salt Hypertension JOURNAL=Frontiers in Immunology VOLUME=4 YEAR=2013 URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2013.00219 DOI=10.3389/fimmu.2013.00219 ISSN=1664-3224 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.