title: An oral formulation of angiotensin-(1-7) reverses corpus cavernosum damages induced by hypercholesterolemia.
abstract: BACKGROUND
  The renin angiotensin system plays a crucial role in erectile function. It has been shown that elevated angiotensin-II levels contribute to the development of erectile dysfunction (ED). Oppositely, angiotensin-(1-7) (Ang-[1-7]) mediates penile erection by activation of receptor Mas. Recently, we have developed a formulation based on Ang-(1-7) inclusion in cyclodextrin (CyD) [Ang-(1-7)-CyD], which allows for the oral administration of Ang-(1-7).
  
  
  OBJECTIVE
  In the present study, we evaluated the effects of chronic treatment with Ang-(1-7)-CyD on penile fibrosis, oxidative stress, and endothelial function in hypercholesterolemic mice.
  
  
  METHODS
  Apolipoprotein(Apo)E-/- mice fed a Western-type diet for 11 weeks received Ang-(1-7)-CyD or vehicle during the final 3 weeks. Collagen content and reactive oxygen species (ROS) production within the corpus cavernosum were evaluated by Sirius red and dihydroethidium staining, respectively. Protein expression of neuronal nitric oxide synthase (nNOS) and endothelial nitric oxide synthase (eNOS), nicotinamide adenine dinucleotide phosphate (NADPH) subunits (p67-phox and p22-phox), and AT1 and Mas receptors in the penis was assessed by Western blotting. Nitric oxide (NO) production was measured by Griess assay in the mice serum. Cavernosal strips were mounted in an isometric organ bath to evaluate the endothelial function.
  
  
  METHODS
  The effect of Ang-(1-7)-CyD treatment on penile fibrosis, oxidative stress, and endothelial function in hypercholesterolemia-induced ED.
  
  
  RESULTS
  Ang-(1-7)-CyD treatment reduced collagen content in the corpus cavernosum of ApoE-/- mice. This effect was associated with an attenuation of ROS production and a diminished expression of NADPH. Furthermore, Ang-(1-7)-CyD treatment augmented the expression of nNOS and eNOS in the penis and elevated vascular NO production. Importantly, these effects were accompanied by an improvement in cavernosal endothelial function.
  
  
  CONCLUSIONS
  Long-term treatment with Ang-(1-7)-CyD reduces penile fibrosis associated with attenuation of oxidative stress. Additionally, cavernosal endothelial function in hypercholesterolemic mice was markedly improved. These results suggest that Ang-(1-7)-CyD might have significant therapeutic benefits for the treatment of erectile dysfunction.
authors.affiliation: Institute of Bioengineering, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
authors.forename: Rodrigo A
authors.initials: RA
authors.lastname: Fraga-Silva
authors.forename: Fabiana P
authors.initials: FP
authors.lastname: Costa-Fraga
authors.forename: Silvia Q
authors.initials: SQ
authors.lastname: Savergnini
authors.forename: Frederico B
authors.initials: FB
authors.lastname: De Sousa
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Montecucco
authors.forename: Daniele
authors.initials: D
authors.lastname: da Silva
authors.forename: Ruben D
authors.initials: RD
authors.lastname: Sinisterra
authors.forename: François
authors.initials: F
authors.lastname: Mach
authors.forename: Nikolaos
authors.initials: N
authors.lastname: Stergiopulos
authors.forename: Rafaela F
authors.initials: RF
authors.lastname: da Silva
authors.forename: Robson A S
authors.initials: RA
authors.lastname: Santos
mesh_terms: D000284:Administration, Oral; D000803:Angiotensin I / Q000008:administration & dosage*; D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics; D003094:Collagen / Q000378:metabolism; D003505:Cyclodextrins / Q000008:administration & dosage*; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D005355:Fibrosis; D006937:Hypercholesterolemia / Q000150:complications* / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D018783:Impotence, Vasculogenic / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009569:Nitric Oxide / Q000097:blood; D052248:Nitric Oxide Synthase Type I / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D010410:Penile Erection / Q000187:drug effects*; D010413:Penis / Q000098:blood supply / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D010446:Peptide Fragments / Q000008:administration & dosage*; D010750:Phosphoproteins / Q000378:metabolism; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism; D014664:Vasodilation / Q000187:drug effects; D014665:Vasodilator Agents / Q000008:administration & dosage*
chemical_list: D001057:Apolipoproteins E; D003505:Cyclodextrins; D010446:Peptide Fragments; D010750:Phosphoproteins; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins; D017382:Reactive Oxygen Species; D044140:Receptor, Angiotensin, Type 1; D043562:Receptors, G-Protein-Coupled; D014665:Vasodilator Agents; C079789:neutrophil cytosol factor 67K; D009569:Nitric Oxide; D003094:Collagen; D000803:Angiotensin I; D052248:Nitric Oxide Synthase Type I; D052250:Nitric Oxide Synthase Type III; C496321:Nos1 protein, mouse; C496315:Nos3 protein, mouse; C118790:angiotensin I (1-7)
keywords: Angiotensin-(1-7); Erectile Dysfunction; Fibrosis; Hydroxypropyl-Cyclodextrin; Hypercholesterolemia; Mas Receptor; Oxidative Stress