**Enzyme Inhibition**

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

Nildris Cruz-Diaz , Bryan A. Wilson and Mark C. Chappell Nildris Cruz-Diaz, Bryan A. Wilson and Mark C. Chappell

Additional information is available at the end of the chapter Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/65949

#### **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 (AT1R) 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-AT1R 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)-AT7R pathway that opposes the Ang II-AT1R 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.

**Keywords:** angiotensin-(1-7), neprilysin, dipeptidyl peptidase 3, ACE, ACE2, renin

### **1. Introduction**

The renin-angiotensin system (RAS) has been long defined as a circulating endocrine system composed of an enzymatic cascade that includes renin to initiate the RAS through the conversion of the large precursor protein angiotensinogen (>350 amino acids) to the inactive decapeptide Ang I and the subsequent generation of the bioactive octapeptide Ang II by

© 2017 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2017 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

angiotensin-converting enzyme (ACE) (**Figure 1**). Ang II binds to the angiotensin type 1 receptor (AT1R) to mediate both peripheral and central mechanisms in the regulation of blood pressure. Activation of the ACE-Ang II-AT1R pathway is also associated with various pathological responses including fibrosis, inflammation, metabolic dysregulation, heart failure, cancer, aging, and diabetic injury [1–5]. Indeed, the targeting of this pathway by biochemical approaches that block the formation of Ang II through ACE inhibitors or binding of Ang II to the AT1R by receptor antagonists is an effective therapy for the treatment of cardiovascular disease. It is now evident that these therapies have revealed alternative pathways within the RAS that may contribute to the beneficial actions of the RAS blockade. For example, the targeting of ACE reduces Ang II expression, but markedly enhances the circulating levels of Ang-(1-7), a ligand for the AT7/MasR that generally opposes the actions of the Ang II-AT1R pathway [6, 7]. The chronic treatment with AT1R antagonists may also increase the formation of Ang-(1-7) through ACE2, as well as shunt Ang II to the AT2R pathway that shares similar properties to the Ang-(1-7) system [8, 9]. Since the RAS is now viewed as a more complex array of components that can be functionally partitioned into distinct receptors and peptide ligands, we present an overview of the peptidases the may constitute the alternative Ang-(1-7) axis of the RAS. We include a discussion of renin, ACE, and chymase as they pertain to the formation of the substrates Ang I and Ang II for the direct processing to Ang-(1-7), as the well as the role of ACE to metabolize Ang-(1-7).

**Figure 1.** Processing cascade for angiotensin-(1-7). Renin cleaves angiotensinogen to Ang I which is further processed to the biologically active peptides Ang II by ACE or chymase (CHYM). Ang II undergoes further processing by the carboxypeptidase ACE2 to form Ang-(1-7). Ang-(1-7) is formed directly through non-Ang II pathways by the direct processing of Ang I by the endopeptidases neprilysin (NEP) and thimet oligopeptidase (TOP). Ang-(1-7) is subsequently metabolized by ACE to Ang-(1-5) and dipeptidyl peptidase 3 (DPP3) to Ang-(3-7) and Ang-(5-7). Adapted from Chappell [54].
