An Increased Arginase Activity Is Associated with Corpus Cavernosum Impairment Induced by Hypercholesterolemia

Abstract

Introduction 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. Aim In the present study, we investigated the activity and role of arginase in the corpus cavernosum of hypercholesterolemic mice. Methods 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. Main Outcome Measure Arginase activity and its role in modulating NO and ROS production within the corpus cavernosum of hypercholesterolemic mice is the main outcome measure. Results 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. Conclusion These evidences indicate that arginase hyperactivity is associated with ED induced by hypercholesterolemia, suggesting that this enzyme is a potential target for treating ED.

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“…Studies in humans and animals have suggested a link between increased cavernosal arginase activity and erectile dysfunction [16, 56, 57]. Inhibition of arginase enhances relaxation of cavernosal smooth muscle cells [58, 59]. Whereas NO production from the endothelium and nitrergic nerves regulates intrinsic tone, arginase activity in CC modulates tone by inhibiting NO production, presumably by competiting with NOS for L-arginine.…”

Evaluation of onion as a functional ingredient in the prevention of metabolic impairments associated to diet-induced hypercholesterolaemia using a multiplatform approach based on LC-MS, CE-MS and GC-MS

“…L-arginine is described as one of the most abundant free amino acid in onion (Hansen, 2001). It has also been reported that plasma arginine levels are strongly related to the severity of inflammation (van Waardenburg, de Betue, Luiking, Engel, & Deutz, 2007), and arginase hyperactivity may be associated with hypercholesterolaemia (Fraga-Silva et al, 2014). A decreased arginine plasma concentration in the HC-fed rats was also found, while in HCO-fed rats the arginine plasma concentration was increased, reaching the C levels.…”

Engineering synthetic optogenetic networks for biomedical applications

“…Erectile dysfunction can occur due to both physiological and psychological reasons including diabetes, kidney disease, chronic alcoholism, multiple sclerosis, atherosclerosis, vascular disease, and neurologic disease [69][70][71][72]. cGMP specific phosphodiesterase inhibitors such as Viagra® have been used to treat erectile dysfunction by suppressing cGMP and extending erection time.…”