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Hypercholesterolemia is a prevalent risk factor for the development of erectile dysfunction (ED), mostly due to an increase in oxidative stress and impaired nitric oxide (NO) bioavailability within the penis. Arginase is an enzyme that shares the common substrate L-arginine with NO synthase. Augmented arginase activity reduces NO production and is associated with ED development. However, the contribution of arginase hyperactivity in hypercholesterolemia-induced ED is unknown.In the present study, we investigated the activity and role of arginase in the corpus cavernosum of hypercholesterolemic mice.Apolipoprotein E (ApoE) gene-deleted mice fed with a Western-type diet for 11 weeks were treated with the selective arginase inhibitor, N-ω-Hydroxy-L-norarginine (NOHA), or vehicle (saline 0.9%) during the last 9 weeks. Arginase activity and expression were measured in penis protein extraction. Reactive oxygen species (ROS) content within the corpus cavernosum was measured by dihydroethidium staining. Functional in vitro studies were performed using cavernosal strips mounted in an isometric organ bath to evaluate NO production.Arginase activity and its role in modulating NO and ROS production within the corpus cavernosum of hypercholesterolemic mice is the main outcome measure.Total arginase activity and arginase type II protein expression were increased in hypercholesterolemic mice compared with wild-type mice. The long-term treatment with NOHA normalized this alteration. Moreover, pharmacological arginase inhibition by NOHA attenuated the augmented ROS production within the corpus cavernosum of ApoE−/− mice, which increased the NO-dependent response in cavernosal strips.These evidences indicate that arginase hyperactivity is associated with ED induced by hypercholesterolemia, suggesting that this enzyme is a potential target for treating ED. Fraga-Silva RA, Costa-Fraga FP, Faye Y, Sturny M, Santos RAS, da Silva RF, and Stergiopulos N. An increased arginase activity is associated with corpus cavernosum impairment induced by hypercholesterolemia. J Sex Med 2014;11:1173–1181.