Abstract 270: Arginase I Deletion Blocks Age-Related Enhancement of Vascular Stiffness and Endothelial Dysfunction

Abstract

Vascular stiffening, decreased nitric oxide (NO) bioavailability and vascular endothelial dysfunction (ED) are markers of the aging cardiovascular system. Increased vascular stiffness and ED are predictors for adverse cardiovascular outcomes. Increased vascular arginase activity has been noted to accompany aging-induced endothelial dysfunction (ED). Therefore, we hypothesized that enhanced arginase activity is involved in age-related increases in arterial stiffness and ED and that limiting the activity of arginase I (Arg I) would reduce this pathology. We tested this hypothesis by analysis of vascular stiffness and ED in aortas from old (12-month) and young (3-month) male wild type (WT) mice and mice lacking one copy of arginase I (Arg I +/- KO). In vivo studies measured vascular stiffness by pulse wave velocity (PWV) and systolic blood pressure (SBP) by tail cuff. Vascular endothelial function studies also were performed ex vivo using myography. Arginase activity assay showed that activity in the aged WT mice was 1.47-fold greater than that in the young WT mice. PWV was markedly increased in old WT mice (1.96±0.28 m/s) compared to young WT mice (1.08±0.10 m/s). By contrast, PWV remained normal in old Arg I +/- KO mice (1.15±0.08 m/s). Endothelium (NO)-dependent vasorelaxation to acetylcholine (ACh) was significantly reduced in the old WT mice as compared with young WT mice (maximum relaxation (MR) of 60±3% vs 78±4%, respectively). This age-induced impairment was markedly blunted in aged Arg I +/- KO mice (MR: 71±3%). The arginase inhibitor BEC (100 μM) also reversed the impairment in ACh-induced vasorelaxation in old WT mice (P<0.05). No differences were observed in endothelial-independent relaxation to SNP among the groups. SBP was also unchanged. In conclusion, deletion of one copy of Arg I prevents ED and reduces vascular stiffness in aging. Thus, reduction of arginase I function may serve as a therapeutic target for normalizing arterial stiffness and preventing vascular dysfunction in aging.