Diminazene Protects Corpus Cavernosum Against Hypercholesterolemia-Induced Injury

Abstract

Introduction. Angiotensin-converting enzyme 2 (ACE2) is a key enzyme of the renin angiotensin system, which breaks down angiotensin II and forms angiotensin-(1-7). In erectile tissues, it has been documented that angiotensin II contributes to the development of erectile dysfunction (ED), while treatment with angiotensin-(1-7) improves penile erection. However, the expression and function of ACE2 in erectile tissues have never been investigated. Aim. Here, we examined the expression of ACE2 in erectile tissues and its actions against hypercholesterolemia-induced corpus cavernosum (CC) injury. Methods. Hypercholesterolemic apolipoprotein E knockout (ApoE −/−) mice, a well-known model of ED, were treated with diminazene aceturate (DIZE), an ACE2 activator compound, or vehicle for 3 weeks. Reactive oxygen species (ROS), collagen content, and protein expression of ACE2, neuronal nitric oxide synthase (nNOS), endo-thelial nitric oxide synthase (eNOS), nicotinamide adenine dinucleotide phosphate-oxidase (NADPH) subunits were evaluated in the penis of DIZE-treated and untreated ApoE −/− mice. Functional studies were performed in CC strips. Main Outcome Measures. ACE2 expression and its role in modulating nitric oxide (NO)/ROS production and fibrosis within the CC of hypercholesterolemic mice were the main outcome measures. Results. ACE2 was expressed in smooth muscle and endothelial cells of mouse CC. Interestingly, ACE2 was downregulated in penis of hypercholesterolemic mice with ED, suggesting a protective role of ACE2 on the CC homeostasis. In accordance with that, pharmacological ACE2 activation by DIZE treatment reduced ROS production and NADPH oxidase expression, and elevated nNOS and eNOS expression and NO bioavailability in the penis of ApoE −/− mice. Additionally, DIZE decreased collagen content within the CC. These beneficial actions of DIZE on the CC were not accompanied by improvements in atherosclerotic plaque size or serum lipid profile. Conclusion. ACE2 is expressed in erectile tissue and its reduction is associated with hypercholesterolemia-induced ED. Additionally, treatment with DIZE improved hypercholesterolemia-induced CC injury, suggesting ACE2 as a potential target for treating ED. Fraga-Silva RA, Costa-Fraga FP, Montecucco F, Sturny M, Faye Y, Mach F, Pelli G, Shenoy V, da Silva RF, Raizada MK, Santos RAS, and Stergiopulos N. Diminazene protects corpus cavernosum against hypercholesterolemia-induced injury. J Sex Med 2015;12:289-302.

Diminazene enhances stability of atherosclerotic plaques in ApoE-deficient mice

“…Diminazene actions on the cardiovascular system have been documented in different conditions. For instance, diminazene attenuates pulmonary hypertension [27], reduces damages in cardiac [41] and stroke ischemia [42], improves erectile function [43], as well as other beneficial effects [44,45]. …”

The ACE2/Angiotensin-(1–7)/MAS Axis of the Renin-Angiotensin System: Focus on Angiotensin-(1–7)

“…XNT adminstration also prevented the increase in right ventricular systolic pressure and hypertrophy in a monocrotaline-induced pulmonary hypertension model (169) and attenuated thrombus formation in SHR (190). Numerous protective effects have been reported with diminazene aceturate (DIZE), another putative ACE2 activator (102,118,119,184,186,335,341,357,429,445,511,513,535,566). It should be pointed out, however, that the beneficial effects of these small-molecule activators might also depend on ACE2-independent mechanisms (234).…”

Apelin‐13 treatment enhances the stability of atherosclerotic plaques

“…The intraplaque reactive oxygen species (ROS) detection was performed by dihydroethidium (DHE; Sigma-Aldrich, St. Louis, MO, USA, cat# 37291) staining, as previously described. 18 Cryosections of aortic roots, OSS-and LSS carotids were thawed at room temperature and sequentially washed with PBS. Subsequently, the sections were incubated with DHE at 2 lmol/L in PBS for 20 minutes in a dark humid chamber at 37°C.…”