E ndothelial cells play a central role in maintaining vascular

1238  Hypertension  June 

2013

Endothelial dysfunction and elevated blood pressure in MAS gene-deleted 

mice. Hypertension. 2008;51:574–580.

 17.  Hernández Prada JA, Ferreira AJ, Katovich MJ, Shenoy V, Qi Y, Santos 

RA, Castellano RK, Lampkins AJ, Gubala V, Ostrov DA, Raizada MK. 

Structure-based identification of small-molecule angiotensin-converting 

enzyme 2 activators as novel antihypertensive agents. Hypertension. 

2008;51:1312–1317.

 18. Ferreira AJ, Shenoy V, Qi Y, Fraga-Silva RA, Santos RA, Katovich 

MJ, Raizada MK. Angiotensin-converting enzyme 2 activation protects 

against hypertension-induced cardiac fibrosis involving extracellular sig-

nal-regulated kinases. Exp Physiol. 2011;96:287–294.

 19. Ferreira AJ, Shenoy V, Yamazato Y, Sriramula S, Francis J, Yuan L, 

Castellano RK, Ostrov DA, Oh SP, Katovich MJ, Raizada MK. Evidence 

for angiotensin-converting enzyme 2 as a therapeutic target for the 

prevention of pulmonary hypertension. Am J Respir Crit Care Med. 

2009;179:1048–1054.

 20.  Fraga-Silva RA, Sorg BS, Wankhede M, Dedeugd C, Jun JY, Baker MB, 

Li Y, Castellano RK, Katovich MJ, Raizada MK, Ferreira AJ. ACE2 acti-

vation promotes antithrombotic activity. Mol Med. 2010;16:210–215.

 21.  Murça TM, Moraes PL, Capuruço CA, Santos SH, Melo MB, Santos RA, 

Shenoy V, Katovich MJ, Raizada MK, Ferreira AJ. Oral administration 

of an angiotensin-converting enzyme 2 activator ameliorates diabetes-

induced cardiac dysfunction. Regul Pept. 2012;177:107–115.

 22.  Murça TM, Almeida TC, Raizada MK, Ferreira AJ. Chronic activation of 

endogenous angiotensin-converting enzyme 2 protects diabetic rats from 

cardiovascular autonomic dysfunction. Exp Physiol. 2012;97:699–709.

 23.  Zhong J, Guo D, Chen CB, Wang W, Schuster M, Loibner H, Penninger 

JM, Scholey JW, Kassiri Z, Oudit GY. Prevention of angiotensin 

II-mediated renal oxidative stress, inflammation, and fibrosis by angioten-

sin-converting enzyme 2. Hypertension. 2011;57:314–322.

 24.  Dong B, Zhang C, Feng JB, et al. Overexpression of ACE2 enhances 

plaque stability in a rabbit model of atherosclerosis. Arterioscler Thromb 

Vasc Biol

. 2008;28:1270–1276.

 25.  Lovren F, Pan Y, Quan A, Teoh H, Wang G, Shukla PC, Levitt KS, Oudit 

GY, Al-Omran M, Stewart DJ, Slutsky AS, Peterson MD, Backx PH, 

Penninger JM, Verma S. Angiotensin converting enzyme-2 confers endo-

thelial protection and attenuates atherosclerosis. Am J Physiol Heart Circ 

Physiol

. 2008;295:H1377–H1384.

 26.  Oudit GY, Liu GC, Zhong J, Basu R, Chow FL, Zhou J, Loibner H, Janzek 

E, Schuster M, Penninger JM, Herzenberg AM, Kassiri Z, Scholey JW. 

Human recombinant ACE2 reduces the progression of diabetic nephropa-

thy. Diabetes. 2010;59:529–538.

 27.  Kuba K, Imai Y, Penninger JM. Angiotensin-converting enzyme 2 in lung 

diseases. Curr Opin Pharmacol. 2006;6:271–276.

 28.  Silva DM, Vianna HR, Cortes SF, Campagnole-Santos MJ, Santos RA, 

Lemos VS. Evidence for a new angiotensin-(1-7) receptor subtype in the 

aorta of Sprague-Dawley rats. Peptides. 2007;28:702–707.

 29.  Raffai G, Durand MJ, Lombard JH. Acute and chronic angiotensin-(1-7) 

restores vasodilation and reduces oxidative stress in mesenteric arteries of 

salt-fed rats. Am J Physiol Heart Circ Physiol. 2011;301:H1341–H1352.

 30.  Briones AM, Touyz RM. Oxidative stress and hypertension: current con-

cepts. Curr Hypertens Rep. 2010;12:135–142.

 31.  Cai H, Harrison DG. Endothelial dysfunction in cardiovascular diseases: 

the role of oxidant stress. Circ Res. 2000;87:840–844.

 32.  Forbes JM, Coughlan MT, Cooper ME. Oxidative stress as a major culprit 

in kidney disease in diabetes. Diabetes. 2008;57:1446–1454.

What Is New?

•

Our study indicates that activation of intrinsic angiotensin-converting 

enzyme 2, a recently described member of the renin–angiotensin sys-

tem, using a small molecule angiotensin-converting enzyme 2 activator 

named 1-[[2-(dimetilamino)etil]amino]-4-(hidroximetil)-7-[[(4-metilfenil)

sulfonil]oxi]-9H-xantona-9 (XNT) improves endothelial function by de-

creasing the generation of reactive oxygen species.

What Is Relevant?

•

The balance between release and function of endothelium-derived nitric 

oxide and reactive oxygen species production is critical in endothelial 

dysfunction. Therapies targeting the reestablishment of this balance 

might have significant implications in hypertension and cardiovascular 

disease management. Thus, our study proposes angiotensin-converting 

enzyme 2 activation as a potential target for treating hypertension and 

related cardiovascular diseases.

Summary

Our results show that XNT administration ameliorates the endothe-

lial function of hypertensive and diabetic rat vessels by attenuation 

of the oxidative stress. Moreover, XNT elicits an endothelial-depen-

dent vasorelaxation response, which is mediated by Mas.

Novelty and Significance

 by guest on November 6, 2017

http://hyper.ahajournals.org/

Downloaded from 

---

Robson A.S. Santos, Mohan K. Raizada and Anderson J. Ferreira

L. Borges, Ana Paula Nadu, Marilene L. Oliveira, Vinayak Shenoy, Michael J. Katovich,

Augusto Martins Lima, Roberto Q. Lautner, Carlos H. Castro, Célia Maria A. Soares, Clayton 

Rodrigo A. Fraga-Silva, Fabiana P. Costa-Fraga, Tatiane M. Murça, Patrícia L. Moraes,

Angiotensin-Converting Enzyme 2 Activation Improves Endothelial Function

Print ISSN: 0194-911X. Online ISSN: 1524-4563 

Copyright © 2013 American Heart Association, Inc. All rights reserved.

is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231

Hypertension 

doi: 10.1161/HYPERTENSIONAHA.111.00627

2013;61:1233-1238; originally published online April 22, 2013;

Hypertension. 

 

http://hyper.ahajournals.org/content/61/6/1233

World Wide Web at: 

The online version of this article, along with updated information and services, is located on the

 

http://hyper.ahajournals.org/content/suppl/2013/04/22/HYPERTENSIONAHA.111.00627.DC1

Data Supplement (unedited) at:

  

 

http://hyper.ahajournals.org//subscriptions/

is online at: 

Hypertension 

 Information about subscribing to 

Subscriptions:

  

 

http://www.lww.com/reprints

 Information about reprints can be found online at: 

Reprints:

  

document. 

Permissions and Rights Question and Answer 

this process is available in the

click Request Permissions in the middle column of the Web page under Services. Further information about

Office. Once the online version of the published article for which permission is being requested is located, 

 can be obtained via RightsLink, a service of the Copyright Clearance Center, not the Editorial

Hypertension

in

 Requests for permissions to reproduce figures, tables, or portions of articles originally published

Permissions:

 by guest on November 6, 2017

http://hyper.ahajournals.org/

Downloaded from 

---