E ndothelial cells play a central role in maintaining vascular

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1233

E

ndothelial cells play a central role in maintaining vascular 

homeostasis and their dysfunction is associated with many 

forms of cardiovascular and metabolic diseases.

1

 Diminished 

production and function of endothelium-derived nitric oxide 

and other vasoprotective factors and the exaggerated produc-

tion of reactive oxygen species (ROS) and vasoconstrictors 

eventually lead to endothelial dysfunction, resulting in ele-

vated vascular tone, which contributes to the development and 

progression of cardiovascular and metabolic diseases.

1,2

The renin–angiotensin system is a pivotal modulator of 

the vascular function and its hyperactivity is involved in the 

endothelial dysfunction.

3,4

 The renin–angiotensin system is 

regulated by 2 opposite axes.

5,6

 The effector of the first one 

is angiotensin II (Ang II), which is generated by coordinated 

enzymatic reactions involving, mainly, the angiotensin-

converting enzyme (ACE). This peptide acts primarily through 

the AT

1

 receptor, promoting vasoconstriction, proliferation, 

and oxidative stress.

4,7

 Thus, this axis is composed by ACE, 

Ang II, and AT

1

 receptor. The second axis, formed by ACE2, 

angiotensin-(1–7) [Ang-(1–7)], and Mas,

5

 is activated by 

Ang-(1–7) binding to its own receptor Mas.

8

 Generally, this 

axis promotes opposite effects to those elicited by the ACE/

Ang II/AT

1

 receptor branch.

5,6

 Ang-(1–7) may be generated 

by different enzymatic pathways

9

; however, it has been 

proposed that ACE2 is the main enzyme involved in the Ang-

(1–7) formation.

10,11

 ACE2 is a monocarboxypeptidase that 

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.   

(Hypertension. 2013;61:1233-1238.) 

•

 

Online Data Supplement

Key Words: angiotensin-(1

–

7) 

■

 diabetes mellitus 

■

 endothelium dysfunction 

■

 oxidative stress  

■

 renin

–

angiotensin system

Received November 13, 2012; first decision March 21, 2013; revision accepted April 1, 2013.

From the National Institute of Science and Technology in Nanobiopharmaceutics (NanoBiofar) (R.A.F.-S., A.M.L., R.Q.L., C.H.C., R.A.S.S., A.J.F.), 

Departments of Physiology and Biophysics (F.P.C.-F., A.M.L., R.Q.L., A.P.N., M.L.O., R.A.S.S.) and Morphology (T.M.M., P.L.M., A.J.F.), Federal 

University of Minas Gerais, Belo Horizonte, Brazil; Department of Physiological Sciences, Federal University of Goiás, Brazil (C.H.C., C.M.A.S., C.L.B.); 

and Departments of Pharmacodynamics (V.S., M.J.K.) and Physiology and Functional Genomics (R.A.F.-S., M.K.R.), University of Florida, Gainesville, FL.

The online-only Data Supplement is available with this article at http://hyper.ahajournals.org/lookup/suppl/doi:10.1161/HYPERTENSIONAHA. 

111.00627/-/DC1.

Correspondence to Anderson J. Ferreira, Department of Morphology, Federal University of Minas Gerais, Av. Antônio Carlos, 6627, 31.270-901 Belo 

Horizonte, MG, Brazil. E-mail [e-mail]

Angiotensin-Converting Enzyme 2 Activation  

Improves Endothelial Function

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

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

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

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

© 2013 American Heart Association, Inc.

Hypertension is available at http://hyper.ahajournals.org 

DOI: 10.1161/HYPERTENSIONAHA.111.00627

Renin-Angiotensin System

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