Abstract 885: Arginase Promotes Endothelial Dysfunction and Hypertension in Obesity
Endothelial dysfunction (ED) resulting from impaired nitric oxide (NO) synthesis is a salient feature in obesity and contributes to the development of cardiovascular disease, including hypertension. Recently, we reported that arginase, which metabolizes L-arginine to L-ornithine and urea, competes with endothelial NO synthase (eNOS) for substrate, L-arginine, and triggers ED in salt-sensitive hypertension. This study tests the hypothesis that arginase contributes to ED and hypertension by limiting L-arginine availability in obese Zucker rats (ZR), which are a well-established genetic model of obesity. Male obese (516 ± 8g) ZR display a significant increase in plasma (5.2 ± 0.3-fold) and vascular (57.6 ± 6.1%) arginase activity that is associated with a selective 2.2 ± 0.1-fold rise in vascular arginase I protein expression compared to age-and sex-matched lean (344 ± 8g) ZR. In contrast, arginase II and eNOS protein levels are unchanged in obese ZR. In obese ZR, the vasodilation of isolated, first-order gracilis muscle arterioles to acetylcholine (Δmax lean: 62 ± 7 vs obese 32 ± 4 μm) and luminal flow (Δmax lean: 22 ± 2 vs obese −3 ± 2 μm) are significantly impaired. However, acute in vitro pretreatment of arterioles with the arginase inhibitor S-(2-boronoethyl)-L-cysteine (BEC; 100μM) or L-arginine (1mM) restores endothelium-dependent dilation in obese ZR, and abolishes the difference between the obese and lean animals. However, D-arginine (1mM), which is not a substrate for eNOS, fails to restore endothelium-dependent dilation in obese ZR. Finally, obese ZR develop hypertension (158 ± 5mmHg) that is reversed by the daily administration of L-arginine (10g/L) in the drinking water (118 ± 5 mmHg) or by the chronic intraperitoneal administration of BEC (55.6μg/hour) via an osmotic minipump (115 ± 6mmHg) for one week. In contrast, the blood pressure of awake lean ZR (116 ± 4mmHg) is unaffected by either the chronic administration of L-arginine (112 ± 3mmHg) or BEC (111 ± 5mmHg). In conclusion, the present study indicates that obesity promotes ED and hypertension by restricting L-arginine availability via the induction of arginase I, and identifies arginase I as a novel therapeutic target in treating vascular disease.