New cardiovascular and pulmonary therapeutic strategies based on the Angiotensin-converting enzyme 2/angiotensin-(1-7)/mas receptor axis

Anderson J Ferreira, Tatiane M Murça, Rodrigo A Fraga-Silva, Carlos Henrique Castro, Mohan K Raizada, Robson A S Santos, Anderson J Ferreira, Tatiane M Murça, Rodrigo A Fraga-Silva, Carlos Henrique Castro, Mohan K Raizada, Robson A S Santos

Abstract

Angiotensin (Ang)-(1-7) is now recognized as a biologically active component of the renin-angiotensin system (RAS). The discovery of the angiotensin-converting enzyme homologue ACE2 revealed important metabolic pathways involved in the Ang-(1-7) synthesis. This enzyme can form Ang-(1-7) from Ang II or less efficiently through hydrolysis of Ang I to Ang-(1-9) with subsequent Ang-(1-7) formation. Additionally, it is well established that the G protein-coupled receptor Mas is a functional ligand site for Ang-(1-7). The axis formed by ACE2/Ang-(1-7)/Mas represents an endogenous counter regulatory pathway within the RAS whose actions are opposite to the vasoconstrictor/proliferative arm of the RAS constituted by ACE/Ang II/AT(1) receptor. In this review we will discuss recent findings concerning the biological role of the ACE2/Ang-(1-7)/Mas arm in the cardiovascular and pulmonary system. Also, we will highlight the initiatives to develop potential therapeutic strategies based on this axis.

Figures

Figure 1
Figure 1
Schematic representation of the renin-angiotensin system (RAS) cascade. The counterregulatory axes of the RAS are composed by ACE/Ang II/AT1 and ACE2/Ang-(1–7)/Mas. ACE: angiotensin-converting enzyme; Ang: angiotensin; AT1: Ang II type 1 receptor; AT2: Ang II type 2 receptor; Mas: Ang-(1–7) receptor; PCP: prolylcarboxypeptidase; PEP: prolyl-endopeptidase; NEP: neutral-endopeptidase 24.11.
Figure 2
Figure 2
Effects of Ang II and Losartan on arterial blood pressure of rats chronically treated with XNT. The responses to increasing doses of Ang II were similar in vehicle- and XNT-treated (a) normotensive (Wistar-Kyoto rats—WKY) and (b) hypertensive (spontaneously hypertensive rats—SHR) rats. Likewise, the response to Losartan (0.25 mg/kg) was similar in vehicle- and XNT-treated (c) normotensive (WKY) and (d) hypertensive (SHRs) rats. The blood pressure was measured through a catheter inserted into the carotid artery and Ang II and Losartan were administrated in bolus using the jugular vein.
Figure 3
Figure 3
Schematic diagram showing the therapeutic strategies to modulate the activity of the renin-angiotensin system (RAS). In addition to the classical RAS blockers, that is, ACE inhibitors and AT1 receptor blockers, the figure highlights the renin inhibitors, the Ang-(1–7) formulations [HPβCD/Ang-(1-7) and cyclic Ang-(1-7)], the synthetic Mas receptor agonists (AVE 0991 and CGEN-856S), and the ACE2 activator (XNT). ACE: angiotensin-converting enzyme; AT1: Ang II type 1 receptor; AT2: Ang II type 2 receptor; Mas: Ang-(1–7) receptor; NEP: neutral-endopeptidase 24.11.

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