Angiotensin-converting enzyme 2 activation improves endothelial function
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Data
2013-06
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Resumo
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.
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Angiotensin-(1 – 7), Diabetes mellitus, Endothelium dysfunction, Oxidative stress, Renin – angiotensin system
Citação
FRAGA-SILVA, Rodrigo A.; COSTA-FRAGA, Fabiana P.; MURCA, Tatiane M.; MORAES, Patrícia L.; MARTINS, Augusto Martins; LAUTNER, Roberto Q.; CASTRO, Carlos H.; SOARES, Célia Maria A.; BORGES, Clayton L.; NADU, Ana Paula; OLIVEIRA, Marilene L.; SHENOY, Vinayak; KATOVICH, Michael J.; SANTOS, Robson A. S.; RAIZADA, Mohan K.; FERREIRA, Anderson J. Angiotensin-converting enzyme 2 activation improves endothelial function. Hypertension, Dallas, v. 61, n. 6, p. 1233-1238, June 2013.