title: Angiotensin-converting enzyme 2 activation improves endothelial function.
abstract: Diminished release and function of endothelium-derived nitric oxide coupled with increases in reactive oxygen species production is critical in endothelial dysfunction. Recent evidences have shown that activation of the protective axis of the renin-angiotensin system composed by angiotensin-converting enzyme 2, angiotensin-(1-7), and Mas receptor promotes many beneficial vascular effects. This has led us to postulate that activation of intrinsic angiotensin-converting enzyme 2 would improve endothelial function by decreasing the reactive oxygen species production. In the present study, we tested 1-[[2-(dimetilamino)etil]amino]-4-(hidroximetil)-7-[[(4-metilfenil)sulfonil]oxi]-9H-xantona-9 (XNT), a small molecule angiotensin-converting enzyme 2 activator, on endothelial function to validate this hypothesis. In vivo treatment with XNT (1 mg/kg per day for 4 weeks) improved the endothelial function of spontaneously hypertensive rats and of streptozotocin-induced diabetic rats when evaluated through the vasorelaxant responses to acetylcholine/sodium nitroprusside. Acute in vitro incubation with XNT caused endothelial-dependent vasorelaxation in aortic rings of rats. This vasorelaxation effect was attenuated by the Mas antagonist D-pro7-Ang-(1-7), and it was reduced in Mas knockout mice. These effects were associated with reduction in reactive oxygen species production. In addition, Ang II-induced reactive oxygen species production in human aortic endothelial cells was attenuated by preincubation with XNT. These results showed that chronic XNT administration improves the endothelial function of hypertensive and diabetic rat vessels by attenuation of the oxidative stress. Moreover, XNT elicits an endothelial-dependent vasorelaxation response, which was mediated by Mas. Thus, this study indicated that angiotensin-converting enzyme 2 activation promotes beneficial effects on the endothelial function and it is a potential target for treating cardiovascular disease.
authors.affiliation: National Institute of Science and Technology in Nanobiopharmaceutics, Federal University of Minas Gerais, Av. Antônio Carlos, 6627, 31.270-901 Belo Horizonte, MG, Brazil.
authors.forename: Rodrigo A
authors.initials: RA
authors.lastname: Fraga-Silva
authors.forename: Fabiana P
authors.initials: FP
authors.lastname: Costa-Fraga
authors.forename: Tatiane M
authors.initials: TM
authors.lastname: Murça
authors.forename: Patrícia L
authors.initials: PL
authors.lastname: Moraes
authors.forename: Augusto
authors.initials: A
authors.lastname: Martins Lima
authors.forename: Roberto Q
authors.initials: RQ
authors.lastname: Lautner
authors.forename: Carlos H
authors.initials: CH
authors.lastname: Castro
authors.forename: Célia Maria A
authors.initials: CM
authors.lastname: Soares
authors.forename: Clayton L
authors.initials: CL
authors.lastname: Borges
authors.forename: Ana Paula
authors.initials: AP
authors.lastname: Nadu
authors.forename: Marilene L
authors.initials: ML
authors.lastname: Oliveira
authors.forename: Vinayak
authors.initials: V
authors.lastname: Shenoy
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Katovich
authors.forename: Robson A S
authors.initials: RA
authors.lastname: Santos
authors.forename: Mohan K
authors.initials: MK
authors.lastname: Raizada
authors.forename: Anderson J
authors.initials: AJ
authors.lastname: Ferreira
mesh_terms: D000085962:Angiotensin-Converting Enzyme 2; D000818:Animals; D001013:Aorta, Thoracic / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism / Q000503:physiopathology; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology*; D004789:Enzyme Activation; D006801:Humans; D006973:Hypertension / Q000188:drug therapy / Q000201:enzymology / Q000503:physiopathology*; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D018384:Oxidative Stress; D007703:Peptidyl-Dipeptidase A / Q000187:drug effects / Q000378:metabolism*; D011863:Radioimmunoassay; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000037:antagonists & inhibitors / Q000378:metabolism; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology*; D044004:Xanthones / Q000494:pharmacology
chemical_list: C541435:1-((2-dimethylamino)ethylamino)-4-(hydroxymethyl)-7-((4-methylphenyl)sulfonyloxy)-9H-xanthene-9-one; D017382:Reactive Oxygen Species; D044004:Xanthones; D007703:Peptidyl-Dipeptidase A; C000705307:ACE2 protein, human; C000705328:Ace2 protein, mouse; C000705329:Ace2 protein, rat; D000085962:Angiotensin-Converting Enzyme 2
keywords: angiotensin-(1–7); diabetes mellitus; endothelium dysfunction; oxidative stress; renin–angiotensin system