Arginase Promotes Endothelial Dysfunction and Hypertension in Obesity by Restricting Arginine Bioavailability

Abstract

Obesity is a major risk factor for the development of hypertension. While endothelial dysfunction (ED) has been implicated in obesity-related hypertension, the mechanisms underlying this defect are not fully known. In this study, we investigated whether the arginine-catabolizing enzyme arginase contributes to ED and hypertension in male obese Zucker rats (ZR). Vascular and plasma arginase activity and expression was significantly increased while global arginine bioavailability decreased in obese ZR. Acetylcholine or luminal flow caused dilation of isolated skeletal muscle arterioles but this was reduced or absent in vessels from obese ZR. Treatment of arterioles with arginase inhibitors or L-arginine enhanced vasodilation in obese ZR and abolished differences between lean and obese animals, while D-arginine had no effect. Mean arterial blood pressure was significantly increased in obese ZR. However, administration of arginase inhibitors or L-arginine reversed or prevented the development of hypertension in obese animals, and this was associated with an improvement in systemic arginine bioavailability. In conclusion, the present study demonstrates that arginase promotes ED and hypertension in obesity by reducing arginine bioavailability, and identifies arginase as a promising therapeutic target in ameliorating obesity-related vascular disease. Supported by grants from the NIH (HL-59976 and HL-74966) and AHA (855715G and BGIA 0865241B).