Abstract 1213: Arginase Inhibition Decreases Vascular Stiffness and Increases NO production In Apo E Knock-out Mice
Background: We have previously demonstrated that OxLDL increases arginase (Arg) activity and decreases endothelial NO in human aortic endothelial cells
Hypothesis: Vascular Arg activity is increased in ApoE−/ − (KO) mice and Arg inhibition improves endothelial function.
Methods: 17 WT mice receive normal or high cholesterol (HC) diet. 16 KO mice with HC diet were received 4 weeks of S(2boronethyl)L-cysteine (BEC, 1 mg/mice), a selective inhibitor of Arg, or placebo(P) by osmotic infusion pump (Alzet). Aortic pulse wave velocity (PWV), used to measure vascular stiffness, was acquired by 20MHz pulsed Doppler from arch to abdominal aorta 4 cm below. We also measured Arg activity and NO production in aorta endothelium.
Results: Arg activity was significantly increased and NO production decreased in KO compared to WT; moreover KO BEC mice had a significant decrease in Arg activity and restoration of NO production to WT . PWV was significantly increased in KO vs WT (4.8±0.25 vs 3.9±0.06m/ sec,p < 0.002). Furthermore WT HC mice increased PWV (3.8<0.19 vs 4.5<0.52m/sec, p = 0.03) compared with normal diet (3.8±0.11 vs 4.0±0.11m/sec, p<NS); P treated KO mice had no changes (4.7±0.29 vs 4.8±0.29m/sec, p=NS). In marked contrast, KO BEC mice demonstrated a dramatic decrease in PWV (4.9±0.22 vs 4.0±0.25m/sec, p < 0.03) becoming not similar to WT/normal diet.
Conclusions: This study suggests a pivotal role for Arg in the pathophysiology of endothelial dysfunction. The resultant aortic stiffness in KO mice is likely due to a decrease in endothelial NO production secondary to substrate limitation. Arg represents a novel target for therapy in atherosclerosis, independent of risk factor modification.