Counter-regulatory renin-angiotensin system in cardiovascular disease

Maria Paz Ocaranza, Jaime A Riquelme, Lorena García, Jorge E Jalil, Mario Chiong, Robson A S Santos, Sergio Lavandero, Maria Paz Ocaranza, Jaime A Riquelme, Lorena García, Jorge E Jalil, Mario Chiong, Robson A S Santos, Sergio Lavandero

Abstract

The renin-angiotensin system is an important component of the cardiovascular system. Mounting evidence suggests that the metabolic products of angiotensin I and II - initially thought to be biologically inactive - have key roles in cardiovascular physiology and pathophysiology. This non-canonical axis of the renin-angiotensin system consists of angiotensin 1-7, angiotensin 1-9, angiotensin-converting enzyme 2, the type 2 angiotensin II receptor (AT2R), the proto-oncogene Mas receptor and the Mas-related G protein-coupled receptor member D. Each of these components has been shown to counteract the effects of the classical renin-angiotensin system. This counter-regulatory renin-angiotensin system has a central role in the pathogenesis and development of various cardiovascular diseases and, therefore, represents a potential therapeutic target. In this Review, we provide the latest insights into the complexity and interplay of the components of the non-canonical renin-angiotensin system, and discuss the function and therapeutic potential of targeting this system to treat cardiovascular disease.

Conflict of interest statement

M.P.O., M.C., J.E.J. and S.L. have patents related to the pharmacological effects of angiotensin 1–9. R.A.S.S. has patents related to the pharmacological effects of angiotensin 1–7 and alamandine. J.A.R. and L.G. declare no competing interests.

Figures

Fig. 1. Classical and counter-regulatory renin–angiotensin pathways.
Fig. 1. Classical and counter-regulatory renin–angiotensin pathways.
In the classical system, renin cleaves angiotensinogen to produce angiotensin I. This peptide can be processed by angiotensin-converting enzyme (ACE) to form angiotensin II, which in turn can bind to the type 1 angiotensin II receptor (AT1R) and AT2R. AT1R activation increases aldosterone and anti-diuretic hormone (ADH) production, sympathetic nervous system (SNS) tone, blood pressure, vasoconstriction, cardiac hypertrophy, fibrosis, inflammation, vascular smooth muscle cell (VSMC) dedifferentiation and reactive oxygen species (ROS) production, while decreasing parasympathetic nervous system (PSNS) tone, baroreflex sensitivity, nitric oxide (NO) production and natriuresis. Angiotensin II can be further processed by aminopeptidase A (APA) to form angiotensin III, which also acts through AT1R. Angiotensin III can be cleaved by alanyl aminopeptidase N (APN) to generate angiotensin IV, which binds to AT4R, producing cardioprotective effects, increasing natriuresis and NO production, as well as reducing vasoconstriction, inflammation and VSMC dedifferentiation. Angiotensin I can also be cleaved by ACE2 and neprilysin (NEP) to produce angiotensin 1–9 and angiotensin 1–7, respectively. Angiotensin 1–9 can activate AT2R to trigger natriuresis and NO production, thus mediating vasodilatory effects and reducing blood pressure. In addition, this peptide is cardioprotective and can attenuate inflammation, cardiac hypertrophy and fibrosis. Angiotensin 1–7 binds to the proto-oncogene Mas receptor (MasR) and reduces both blood pressure and noradrenaline release in hypertensive rodents. Conversely, activation of MasR increases NO generation, natriuresis, vasodilatation, PSNS tone and baroreflex sensitivity,. Angiotensin 1–7 can also be formed from angiotensin II cleavage by ACE2 and be further metabolized to alamandine. Alternatively, angiotensin II can be processed by aspartate decarboxylase (AD) to produce angiotensin A, which can be converted to alamandine by ACE2. Upon binding to the Mas-related G protein-coupled receptor member D (MRGD), alamandine can promote the same effects reported for angiotensin 1–7,,, with the exception of natriuresis. RAS, renin–angiotensin system.
Fig. 2. Molecular structures of peptides of…
Fig. 2. Molecular structures of peptides of the counter-regulatory RAS.
The separation of these peptides from a biological sample is difficult, given the similarity of their molecular structures. Angiotensin 1–7 is only two amino acids shorter than angiotensin 1–9, and angiotensin 1–7 and alamandine only differ in their N-terminal amino acid. RAS, renin–angiotensin system.
Fig. 3. Signal transduction mechanisms of the…
Fig. 3. Signal transduction mechanisms of the counter-regulatory RAS.
Signalling through the type 2 angiotensin II receptor (AT2R) can directly inhibit AT1R activation and thus antagonize the effects of angiotensin II. Stimulation of AT2R can also inhibit extracellular signal-regulated kinase 1 (ERK1) and ERK2 by activating Src homology region 2 domain-containing phosphatase 1 (SHP1) and mitogen-activated protein kinase-phosphatase 1 (MKP1), which can result in attenuation of cardiac hypertrophy. AT2R can also activate the transcription factor promyelocytic zinc finger protein (PLZF), thereby inducing the expression of ribosomal protein S6 kinase β1 (p70S6K) and p85α expression and, in turn, eliciting protein synthesis. In addition, AT2R might trigger vasodilatation by activating the phosphatidylinositol-3-kinase (PI3K)–AKT–endothelial nitric oxide synthase (eNOS)–nitric oxide (NO)–cGMP pathway either via angiotensin 1–9-mediated activation– or by heterodimerization with bradykinin B2 receptor (B2R). Phosphorylation of AKT by activation of AT2R through angiotensin 1–9 binding has also been found to confer cardioprotection. Angiotensin 1–7 might induce the NO–soluble guanylyl cyclase pathway, thereby triggering vasodilatation via proto-oncogene Mas receptor (MasR) activation. Activation of this receptor can also reduce cardiac fibrosis by stimulating SHP1 and dual-specificity phosphatase (DUSP), consequently inhibiting p38 mitogen-activated protein kinase (MAPK) and ERK1 and ERK2. The KCa3.1 channel and mothers against decantaplegic homologue 2 (SMAD2) and SMAD3 are downstream targets of ERK1 and ERK2, and are downregulated upon MasR activation. Additionally, angiotensin 1–7 exerts an anti-hypertrophic effect by inhibiting nuclear factor of activated T cells (NFAT) through a MasR–PI3K–AKT–NO–cGMP-dependent pathway. This anti-hypertrophic effect also depends on atrial natriuretic peptide (ANP) secretion during atrial pacing and is associated with activation of the Na+/H+ exchanger (NHE1) and calcium/calmodulin-dependent protein kinase II (CaMKII) via the PI3K–AKT pathway. Cardiac hypertrophy can also be reduced by activation of the Mas-related G protein-coupled receptor member D (MRGD) by alamandine via adenylate cyclase (AC)–cAMP–protein kinase A (PKA) signalling.

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