Abstract 186: ACE2 Activation Protects Corpus Cavernosum Impairment Induced by Hypercholesterolemia

Abstract

Erectile dysfunction (ED) is multicausal disorder strictly associated with cardiovascular diseases. ACE2 is a key enzyme of the renin angiotensin system which plays an essential role in the cardiovascular system; however, the function of this enzyme in erectile tissues has never been investigated. Here we examined the expression of ACE2 in erectile tissues and its protective actions against hypercholesterolemic-induced corpus cavernosum injures. ACE2 expression was evaluated by immunostaining and western blot. Apolipoprotein E knockout (ApoE-/-) mice fed with Western-type diet for 11 weeks were treated with DIZE, an ACE2 activator compound, or vehicle during the last 3 weeks. Collagen and reactive oxygen species (ROS) content within the corpus cavernosum (CC) were evaluated by Sirius red and dihydroethidium staining, respectively. Protein expression of nNOS, eNOS, NADPH subunits (p67-phox and p22-phox) was assessed by western blot. Functional studies in CC strips were performed in an isometric organ bath. ACE2 was expressed in smooth muscle and endothelial cells of mouse CC. Interestingly, this enzyme was downregulated in penis from hypercholesterolemic mice. The treatment with DIZE reduced ROS production and NADPH oxidase expression in penis from ApoE-/- mice. Furthermore, DIZE treatment elevated vascular NO production (untreated-ApoE-/-: 11.3±1.1 vs. treated-ApoE-/-: 18.7±4.5, mol/L of serum NO3-) and augmented the expression of nNOS and eNOS in the penis. The NO-dependent relaxation induced by acetylcholine (ACh) was significantly increased in CC strip from DIZE-treated ApoE-/- mice (wild type 53.7%; untreated-ApoE-/- 39.3%; treated-ApoE-/- 52.1%, percentage of relaxation at 1μM of ACh). Additionally, DIZE treatment decreased collagen content within the CC. Of note, these beneficial actions of DIZE on the CC were not associated with changes in atherosclerotic plaque deposition or serum lipid profile. In summary, ACE2 activation attenuated oxidative stress, augmented NO bioavailability and decreased collagen deposition in CC of hypercholesterolemic mice. These results demonstrate that ACE2 is expressed and functional in erectile tissue, suggesting that this enzyme might have significant therapeutic benefits against ED.