Key result
Partial deletion of arginase 1 prevented the progressive increase in systolic blood pressure and endothelial dysfunction induced by 6 weeks of DOCA-salt treatment in mice.
Why the study?
Does partial deletion of ARG1 or complete deletion of ARG2 prevent increased blood pressure and vascular endothelial dysfunction in a DOCA-salt mouse model of hypertension?
Does partial deletion of ARG1 or complete deletion of ARG2 prevent increased blood pressure and vascular endothelial dysfunction in a DOCA-salt mouse model of hypertension?
Arginase 1 plays a key role in salt-induced hypertension and vascular dysfunction, suggesting arginase inhibition may be a novel target for antihypertensive therapy.
Answers are grounded in this paper and cite their sources.
Arginase 1 merits exploration as a hypertension target; hypothesis-generating in mice and leaves open human translation.
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.
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Toque et al. (2013) studied Hypertension and vascular endothelial dysfunction. Partial ARG1+/- knockout vs. Wild type mice was evaluated on Systolic blood pressure at 6 weeks (p=<0.05). Partial deletion of arginase 1 prevented the progressive increase in systolic blood pressure and endothelial dysfunction induced by 6 weeks of DOCA-salt treatment in mice.
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