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 anderson@icb.ufmg.br
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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