Angiotensin-Converting Enzyme 2 Activation Improves Endothelial Function

Abstract

Diminished release and function of endothelium-derived nitric oxide (NO) coupled with increases in reactive oxygen species (ROS) 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 enzyme2 (ACE2), Angiotensin-(1-7) [Ang-(1-7)] and Mas receptor promotes many beneficial vascular effects. This has led us to postulate that activation of intrinsic ACE2 would improve endothelial function by decreasing the ROS 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 ACE2 activator, on endothelial function to validate this hypothesis. In vivo treatment with XNT (1mg/kg/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 ROS production. In addition, Ang II-induced ROS production in human aortic endothelial cells was attenuated by pre-incubation 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 ACE2 activation promotes beneficial effects on the endothelial function and it is a potential target for treating cardiovascular disease.

Upregulation of Angiotensin (1-7)-Mediated Signaling Preserves Endothelial Function Through Reducing Oxidative Stress in Diabetes

“…The present study shows that ACE2 overexpression both in vivo and ex vivo by ACE2 adenovirus transduction rescued the impaired EDRs in aortas and FMD in resistance mesenteric arteries from diabetic mice, which was consistent with earlier studies on ApoE -/ -mice and spontaneously hypertensive stroke-prone rats (29,43). Recently, ACE2 priming by the pharmacological activator, xanthenone (XNT), has been shown to protect the function of endothelial progenitor cells in hypertension and diabetes (5,11,18,23). In the present study, we have used a newly discovered ACE2 activator, DIZE (20,40,46), and shown that it enhances ACE2 activity in vitro.…”

Effect of Angiotensin-(1-7) on Aortic Response, TNF-α, IL-1β and Receptor for Advanced Glycation Endproduct in Rat's Adjuvant-Induced Arthritis

“…However, it should be noted that Ang-(1-7) did not relax the denuded aorta by itself when the effect of ACh was tested. This result is similar to that reported in vitro for the MasR agonist [50] and could stem from the importance of intact endothelium in ACh activity.…”

“…Neither AIA nor Ang-(1-7) changed SNP relaxation. The result of Ang-(1-7) is similar to that reported for MasR agonist [50] . These results suggest that AIA does not disturb smooth muscle activity, and Ang-(1-7) activities are not directly displayed via SNP-acted mechanisms in the smooth muscle of aorta.…”

“…This activity of Ang-(1-7) could be attributed to the non-endothelial and possibly direct effect displayed by Ang-(1-7) in the vasculature smooth muscle and includes direct antagonism Ang II [48] and inhibition of Ang II-induced norepinephrine release [49] . This effect could also be attributed to replacement by the administered Ang-(1-7) of that lost by denudation or to improvement of the endothelium dysfunction that was induced by AIA [9] and to decreased production of ROS by Ang-(1-7) [50] . However, it should be noted that Ang-(1-7) did not relax the denuded aorta by itself when the effect of ACh was tested.…”

Heat Shock Prevents Insulin Resistance–Induced Vascular Complications by Augmenting Angiotensin-(1-7) Signaling

“…Studies involving the activation of ACE2 further confirm the role of ANG-(1-7) axis cardiovascular dysfunction. Either pharmacological or genetic activation of ACE2 improved endothelial migration, and impaired tube formation in renin transgenic mice and endothelial dysfunction in SHR rats (57,58). ACE2 activation has been reported to enhance the reparative function of endothelial progenitor cells in the diabetic condition (59).…”