Metabolic syndrome promotes endothelial dysfunction and hypertension via the induction of arginase

Zucker rats (ZR) are a genetic model of metabolic syndrome that exhibit hypertension and endothelial dysfunction (ED) due to decreased nitric oxide (NO) levels. Since L‐arginine is the exclusive substrate for eNOS, its availability regulates NO formation. Recently, we reported that arginase, which metabolizes L‐arginine to L‐ornithine and urea, competes with eNOS for substrate and promotes ED in salt‐sensitive hypertension. This study tests the hypothesis that arginase contributes to ED and hypertension in obese ZR by limiting L‐arginine availability. Obese (524±9g) ZR display increased vascular arginase activity and arginase I protein but unchanged arginase II and eNOS expression relative to lean (299±17g) ZR. In obese ZR, the response of isolated, first‐order gracilis muscle arterioles to acetylcholine (Δ max lean: 62±7 vs obese 32±4 μm) and luminal flow (Δ max lean: 22±2 vs obese −3±2 μm) were greatly attenuated. However, acute in vitro pretreatment with L‐arginine (1mM) or the specific arginase inhibitor S‐(2‐Boronethyl)‐L‐cysteine (BEC, 100μM) restored endothelium‐dependent dilation in obese ZR and abolished the difference between groups. In obese hypertensive ZR (159±4mmHg), administration of L‐arginine to the drinking water (10g/L) or the chronic administration of BEC (55.6 μg/h, ip) for 6 days significantly lowered mean arterial blood pressure to 119±5mmHg and 116±4mmHg, respectively. In conclusion, the present study indicates that metabolic syndrome promotes endothelial dysfunction and hypertension by restricting L‐arginine availability via the induction of arginase I, and identifies arginase as a novel therapeutic target in treating vascular disease. Supported by NIH.