Hypertension Research (2009) 32, 533–536

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REVIEW

Devil and angel in the renin–angiotensin system:

Recent studies have established a new regulatory axis in the renin–angiotensin system (RAS). In this axis, angiotensin
(Ang)-(1–7) is finally produced from Ang I or Ang II by the catalytic activity of angiotensin-converting enzyme 2 (ACE2).
Ang-(1–7) shows actions different from those of AT1 receptor stimulation, such as vasodilatation, natriuresis, anti-proliferation
and an increase in the bradykinin–NO (nitric oxide) system. As the catalytic efficiency of ACE2 is approximately 400-fold higher
with Ang II as a substrate than with Ang I, this axis is possibly acting as a counter-regulatory system against the ACE/Ang II/AT1
receptor axis. The signaling pathway of the ACE2–Ang-(1–7) axis has not yet been totally and clearly understood. However, a
recent report suggests that the Mas oncogene acts as a receptor for Ang-(1–7). Intracellular signaling through Mas is not clear
yet. Several factors such as Akt phosphorylation, protein kinase C activation and mitogen-activated protein (MAP) kinase
inhibition seem to be involved in this signaling pathway. Further investigations are needed to clarify the regulation and
mechanism of action of ACE2 and Ang-(1–7). However, this second axis through ACE2 and Ang-(1–7) in RAS can be an
important target for the therapy of cardiovascular and metabolic disorders.
Hypertension Research (2009) 32, 533–536; doi:10.1038/hr.2009.74; published online 22 May 2009

Keywords: angiotensin; angiotensin-(1–7); angiotensin-converting enzyme; Mas oncogene; receptors

INTRODUCTION many research groups. Santos et al.7 reported that the Mas oncogene is
The renin–angiotensin system (RAS) has a critical role in the cardio- a receptor for Ang-(1–7). There are an increasing number of reports
vascular system. Recent studies on RAS have found various compo- on the role of ACE2, Ang-(1–7) and Mas in the cardiovascular system.
nents and have proposed new axes of signaling pathways. In a classical In this review, an outline of the role and function of ACE2 with
system, angiotensin (Ang) II produced from Ang I by an angiotensin- the Ang-(1–7) pathway is discussed in comparison with the classical
converting enzyme (ACE) is a strong bioactive substance. Ang II binds ACE–Ang II–AT1 receptor axis.
to two major types of receptors, namely, Ang II type 1 (AT1) and
Ang II type 2 (AT2) receptors,1 the signaling pathways of which have ACE, ANG II AND ANGIOTENSIN-II RECEPTORS—CLASSICAL
been well studied, including in the identification of new signaling- RAS AXIS
related molecules, such as AT1 receptor-associated protein (ATRAP)2 Ang II is a well-known bioactive substance involved in the regulation
and AT2 receptor-interacting protein (ATIP).3 In cardiovascular dis- of blood pressure. Ang II is involved in the exaggeration of cardio-
eases, AT2-receptor stimulation seems to antagonize the signaling vascular disease.4 Recent studies indicate that Ang II is also involved in
associated with AT1-receptor stimulation. As the binding affinity of the onset of diabetes and metabolic disorders.8 In classical RAS, Ang II
Ang II for the AT2 receptor does not differ from that for the AT1 is produced from Ang I by the action of ACE. This classical axis can be
receptor, it is considered that AT2-receptor stimulation contributes to called as the ACE–AngII–AT1 receptor axis. Such findings are closely
the beneficial actions of AT1-receptor blockers (ARBs).4 In this related to the development of RAS inhibitors, such as the ACE
context, AT2-receptor agonists, such as compound 21, have been inhibitor and ARB. The major receptor subtypes for Ang II are the
newly developed and are expected to function as useful agents against AT1 and AT2 receptors. The AT1 receptor was cloned in 1991, and this
pathological disorders in the future.5 finding has contributed to the development of ARBs and accelerated
Recently, a new axis of RAS has been established. In this axis, Ang I basic and clinical researches.9 The distribution of the AT1 receptor
is finally converted to Ang-(1–7) by the catalytic activity of ACE2.6,7 covers most organs, whereas AT2-receptor expression is observed in
The mechanisms of action of Ang-(1–7) are still being investigated by only a few organs after birth and is upregulated in pathological states.1

Department of Molecular Cardiovascular Biology and Pharmacology, Ehime University Graduate School of Medicine, Shitsukawa, Tohon, Ehime, Japan
Correspondence: Dr M Horiuchi, Department of Molecular Cardiovascular Biology and Pharmacology, Ehime University Graduate School of Medicine, Shitsukawa, Tohon,
Ehime 791-0295, Japan.
E-mail: [email protected]
Received 30 April 2009; accepted 1 May 2009; published online 22 May 2009
 Role of ACE2 in organ protection
M Iwai and M Horiuchi
534

AT1-receptor stimulation mediates the classical major actions of Ang II, and its receptor were unclear, resulting in the delay of Ang-(1–7)-
and large clinical trials and basic researches have established the concept based researches. Recent reports show that Ang-(1–7) is produced by
of the cardiovascular continuum proposed by Dzau et al.10,11 AT1- ACE2 activity.16,17 ACE2 is reported to be highly expressed in the
receptor stimulation is in fact known to exert hypertension, stroke, heart, kidney and testis. ACE2 is a membrane-associated hydrolase
cardiovascular events and renal diseases (Figure 1). It has also been and it hydrolyzes Ang I to Ang-(1–9) and Ang II to Ang-(1–7)
reported that the blockade of AT1 receptor promotes longevity.12 (Figure 2).18 As Ang-(1–9) can be converted to Ang-(1–7) by ACE
In recent years, efforts have been carried out to produce the or by other peptidases, ACE2 facilitates Ang-(1–7) production by two
inhibitor of RAS. The first trial to produce a renin inhibitor did not separate pathways.19 Ang-(1–7) loses only one amino acid from Ang
succeed for clinical use because of chemical and technical difficulties. II. It might be possible that Ang-(1–7) is a degradation product of Ang
However, these efforts produced the ACE inhibitor. This success II and one of the inactivation mechanisms of Ang II. However, recent
triggered the development of new RAS inhibitors. ACE inhibitors studies indicate that Ang-(1–7) has more active roles in RAS. Ang-
have some adverse effects, such as coughing. In addition, chronic (1–7) causes vasodilation, which antagonizes AT1-receptor stimula-
administration of an ACE inhibitor showed an escape phenomenon, in tion-mediated vasoconstriction. This effect seemed to be mediated by
which the inhibitory action of the ACE inhibitor is strongly attenuated. the bradykinin–NO (nitric oxide) pathway.18,20 Accordingly, these
To solve such problems, ARB has been developed as the second RAS results suggest that Ang-(1–7) antagonized the pressor effect of
inhibitor. As most actions of Ang II are mediated through the AT1 AT1-receptor stimulation, suggesting that it may act as a kind of
receptor, the non-peptide ARB is available and widely used in the AT1-receptor antagonist, thereby resulting in a blood-pressure-low-
treatment of hypertension, and in cardiovascular and renal diseases. ering effect and an organ-protective effect, such as a reduction of
Ang II acts mainly through AT1 receptors, using various signaling cardiac hypertrophy and fibrosis and renal damage (Figure 3). It is
mechanisms. For example, AT1-receptor stimulation increases the reported that a lack of ACE2 accelerates the pressure-overload-induced
influx of extracellular Ca2+ and mobilization of intracellular Ca2+. cardiac dysfunction.21 On the other hand, the Ang-(1–7) agonist,
An increase in the intracellular Ca2+ level activates acute responses,
such as vascular smooth-muscle contraction, and also activates various
kinases, including the mitogen-activated protein (MAP) kinase
pathway, to induce cell-proliferation signaling. AT1-receptor stimu-
lation seems to activate the EGF receptor in the plasma membrane.
Therefore, a part of the action caused by AT1-receptor stimulation is
similar to that caused by Ca2+-mobilizing hormones and by the EGF
family. In contrast, signaling mediated by AT2-receptor stimulation is
transferred mainly by phosphatases.1 Therefore, the action of
AT2-receptor stimulation is considered to be antagonized against
AT1-receptor-mediated signaling. In fact, an antagonizing action or
the counter-regulation of AT2-receptor stimulation has been reported
previously.13–15

ROLES OF ACE2, ANG-(1–7) AND THE MAS AXIS—A NEW RAS

Figure 1 The role of AT1 receptor stimulation in hypertension and organ damage. NO, nitric oxide; CKD, chronic kidney disease.

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 Role of ACE2 in organ protection
M Iwai and M Horiuchi
535

Figure 3 Action of AT1 and AT2 receptors and Mas-mediated signaling. AT1, angiotensin-II type-1 receptor; AT2, angiotensin-II type-2 receptor; NO, nitric oxide.

Figure 4 The balance between ACE and ACE2 activities affects cardiovascular disorders. ACE, angiotensin-converting enzyme; Ang, angiotensin;
AT1, angiotensin-II type-1 receptor; AT2, angiotensin-II type-2 receptor.

AVE0991, was cardioprotective in diabetic rats.22 In addition, Recent studies on the function of ACE2 suggest that ACE2 has an
Ang-(1–7) potentiates bradykinin, either through an AT2-receptor- important role in the severity of lung failure, such as in acute
dependent mechanism or through the inhibition of ACE.23–25 respiratory distress syndrome (ARDS) or in acute lung injury.30
Recent studies have also shown that Ang-(1–7), similar to ACE Moreover, it has been shown that the severe acute respiratory
inhibitors, potentiates the effect of bradykinin by inhibiting the syndrome (SARS) corona virus utilizes ACE2 as an essential receptor
desensitization of its receptor.26,27 It has been discovered that the for cell fusion and for in vivo infections, suggesting that ACE2
catalytic efficiency of ACE2 is approximately 400-fold higher with contributes to SARS pathogenesis.31 These results indicate that
Ang II as a substrate than with Ang I,17 suggesting that this ACE2 activity has an important role not only in cardiovascular
second arm of the system acts as a counter-regulator of the first diseases but also in damages or dysfunctions of other organs. We
arm. Previous reports suggest that olmesartan, an ARB, increased can expect the further studies on ACE2 functions to contribute toward
the plasma concentration of Ang-(1–7) and the cardiac ACE2- a new therapy for organ damages that target this enzyme.
expression level.28,29 Another ARB, losartan, also induced similar A recent report suggests that the Mas oncogene acts as a receptor for
changes; however, its dose was 100-fold higher than that of Ang-(1–7).32,33 Mas is a class of G-protein-coupled receptor contain-
olmesartan,28 suggesting that this effect of ARB is not a class ing 325 amino-acid residues. The expression of Mas is abundantly
effect. A more detailed analysis could show the regulation of ACE2 expressed in the brain and testis. Low levels of Mas expression were
and Mas, which could contribute toward a new drug discovery for also observed in other tissues, such as in the heart, kidney, lung, liver,
regulating RAS. spleen, tongue and in the skeletal muscle.34,35 The studies using

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M Iwai and M Horiuchi
536

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