Peptidases and the Renin-Angiotensin System: The Alternative Angiotensin-(1-7) Cascade

Abstract

The renin-angiotensin system (RAS) constitutes a key hormonal system in the physiological regulation of blood pressure via peripheral and central mechanisms. Dysregulation of the RAS is considered a major factor in the development of cardiovascular pathologies, and pharmacologic blockades of this system by the inhibition of angiotensin-converting enzyme (ACE) or antagonism of the angiotensin type 1 receptor (AT 1 R) are effective therapeutic regimens. The RAS is now defined as a system composed of different angiotensin peptides with diverse biological actions mediated by distinct receptor subtypes. The classic RAS comprises the ACE-Ang II-AT 1 R axis that promotes vasoconstriction, water intake, sodium retention and increased oxidative stress, fibrosis, cellular growth, and inflammation. The nonclassical or alternative RAS is composed primarily of the ACE2-Ang-(1-7)-AT 7 R pathway that opposes the Ang II-AT 1 R axis. In lieu of the complex aspects of this system, the current review assesses the enzymatic cascade of the alternative Ang-(1-7) axis of the RAS.

Saccharomyces boulardii modulates oxidative stress and renin angiotensin system attenuating diabetes-induced liver injury in mice

“…Furthermore, Bosnyak showed that all endogenous angiotensin peptide fragments show a higher affinity for AT2R than Ang II, and they suggest the metabolites act mainly through AT2R while Ang II acts through AT1R 54 . Besides, a large number of studies have shown that the activation of the ACE/Ang II/AT1R pathway is associated with various pathological responses including diabetic injury 55 , and as mentioned before, Ang II interaction with AT1R enhances oxidative stress 56 . Gopal et al showed that Ang II infusion in the liver caused hepatic damage triggering hepatocyte degeneration, hepatic cell apoptosis, sinusoidal dilatation and Based on the histomorphological investigation, we also demonstrated that the number of hepatocytes is decreased in the liver of diabetic mice when compared to the non-diabetic groups, although the liver mass is not reduced.…”

Dipeptidyl peptidase 3 modulates the renin–angiotensin system in mice

“…stress response of mice), further studies will be necessary to investigate a potential fine tuning of blood pressure regulation in DPP3 −/− mice. The unchanged blood pressure also points toward the involvement of the cardioprotective arm of RAS as a compensatory mechanism ( 8 ). In vitro studies using recombinant human DPP3 additionally identified Ang(1–7) and Ang(1–5) as substrates of the enzyme.…”

“…In vitro studies using recombinant human DPP3 additionally identified Ang(1–7) and Ang(1–5) as substrates of the enzyme. Although the level of Ang(1–7) was not significantly increased in the knockout, it is interesting to note that it is the main metabolite of the alternate RAS and plays an important role as physiological antagonist of Ang II, having vasodilatory and antihypertensive properties ( 8 ). Ang(1–7) is produced by carboxyl- or endopeptidases like neutral endopeptidase, prolyl endopeptidase, ACE2, or prolyl carboxypeptidase from Ang I and Ang II and is metabolized to Ang(2–7) and Ang(3–7) by aminopeptidases and to Ang(1–5) by ACE.…”

“…A variety of small bioactive peptides, such as met-enkephalin and angiotensin (I and II), are substrates of DPP3, although the full range of substrate peptides remains undefined ( 1 , 5 ). Consequently, DPP3 has been implicated in pain modulation ( 6 , 7 ) and blood pressure regulation ( 8 , 9 ). In addition, DPP3 exhibits a moonlighting activity in the Keap1 (Kelch-like ECH-associated protein 1)–Nrf2 (nuclear factor erythroid 2-related factor 2) signaling pathway that appears to play a role in stress responses through transcriptional regulation of the antioxidant response element (ARE) ( 10 ).…”

Antioxidant Solution in Combination with Angiotensin-(1-7) Provides Myocardial Protection in Langendorff-Perfused Rat Hearts

“…Beside the classical RAS, which contains the ACE-Ang II-AT1-receptor pathway and leads to vasoconstriction and retention of sodium/water, there is the alternative RAS. It consists of the ACE2-Ang 1-7-MAS-receptor axis, with effects opponent to those of the classical pathway like vasodilatation, antifibrosis, and antiproliferation [ 17 – 19 ]. Considering the heart, a concentration-dependent effect of Ang 1-7 was found in arrhythmias: 220 pmol Ang 1-7/L displayed an antiarrhythmic effect, while a 10-fold higher amount led to proarrhythmic impacts [ 19 ].…”