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Peptides
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Review
a r t i c l e
i n f o
Article history:
Received 23 August 2011
Accepted 7 September 2011
Available online 16 September 2011
Keywords:
Tissue RAS
Renin
Circulating RAS
Vascular tone
Ang-(1-7)
Vascular cells
a b s t r a c t
The reninangiotensin system (RAS), critically involved in the control of blood pressure and volume
homeostasis, is a dual system comprising a circulating component and a local tissue component. The
rate limiting enzyme is renin, which in the circulating RAS derives from the kidney to generate Ang II,
which in turn regulates cardiovascular function by binding to AT1 and AT2 receptors on cardiac, renal
and vascular cells. The tissue RAS can operate independently of the circulating RAS and may be activated
even when the circulating RAS is suppressed or normal. A functional tissue RAS has been identied in
brain, kidney, heart, adipose tissue, hematopoietic tissue, gastrointestinal tract, liver, endocrine system
and blood vessels. Whereas angiotensinsinogen, angiotensin converting enzyme (ACE), Ang I and Ang II
are synthesized within these tissues, there is still controversy as to whether renin is produced locally
or whether it is taken up from the circulation, possibly by the (pro)renin receptor. This is particularly
true in the vascular wall, where expression of renin is very low. The exact function of the vascular RAS
remains elusive, but may contribute to ne-tuning of vascular tone and arterial structure and may amplify
vascular effects of the circulating RAS, particularly in pathological conditions, such as in hypertension,
atherosclerosis and diabetes. New concepts relating to the vascular RAS have recently been elucidated
including: (1) the presence of functionally active Ang-(1-7)-Mas axis in the vascular system, (2) the
importance of the RAS in perivascular adipose tissue and cross talk with vessels, and (3) the contribution
to vascular RAS of Ang II derived from immune and inammatory cells within the vascular wall. The
present review highlights recent progress in the RAS eld, focusing on the tissue system and particularly
on the vascular RAS.
2011 Elsevier Inc. All rights reserved.
Contents
1.
2.
3.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
The classical RAS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Beyond the classical RAS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.1.
Renin/prorenin receptor . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.2.
ACE2, Ang-(1-7), Ang III, Ang IV and other Ang-derived peptides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.3.
Intracellular RAS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.4.
Tissue-based RAS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.
The vascular RAS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5.
Ang-derived peptides in the vascular wall . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
6.
The RAS in perivascular adventitial tissue (PVAT) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
7.
Functional evidence of vascular tissue RAS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
8.
The vascular RAS and hypertension . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
9.
The (patho)physiological signicance of the vascular RAS further considerations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
10. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Conicts of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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1. Introduction
The reninangiotensin system (RAS) is critically involved in the
physiological regulation of blood pressure and volume homeostasis
and in the pathogenesis of hypertension and other cardiovascular
diseases [43,137]. Pharmacological inhibition of the RAS is a major
therapeutic strategy currently used to manage hypertension and to
reduce the risks of cardiovascular events [6]. Since its discovery in
the 1890s the RAS was identied as an endocrine system whereby
circulating kidney-derived renin regulates cardiovascular function
through Ang II binding to its receptors on target tissues [149]. Until
recently this system was accepted as the conventional RAS. However it is now clear that the kidney is not the only source of renin
production and that angiotensin (Ang) peptides may be formed in
tissues and organs that have a blood pressure-independent function.
Genes coding for enzymes and peptides of the RAS are expressed
in many tissues beyond the kidney, including the brain, adrenal
gland, pituitary gland, reproductive tissues, gastrointestinal tract,
hematopoietic tissue, heart and vessels, suggesting the presence
of a functionally active local or tissue RAS [10,24,142]. Functions
of the local RAS remain elusive, but are probably tissue-specic.
The exact role of tissue RAS in human (patho)physiology is still
unclear. The present review provides an update of the classical RAS
and highlights some new concepts, focusing on the tissue RAS and
specically the vascular RAS.
protein tyrosine phosphatase activation, NO generation and signaling through sphingolipids to stimulate vasodilation, natriuresis,
anti-inammatory and anti-brotic actions and inhibition of cell
growth [77,128]. Increased AT2 R expression occurs in pathological
conditions including: hypertension, myocardial infarction, cardiac
failure, renal failure, cerebral ischemia and diabetes, possibly as a
stress response where fetal genes are re-expressed [1,129,134].
GPCRs interact not only with G proteins but also with accessory
proteins, termed GPCR interacting proteins (GIP). GIP specically
associated with AT1 R, called AT1 R-associated protein (ATRAP), acts
as a negative regulator of AT1 R [5] and is expressed in aorta, heart,
lung and kidney. Overexpression leads to decreased cell proliferation. Another GIP, ARAP1 (AT1 R-associated protein 1), is involved
in recycling of the AT1 receptor [92,146]. GPCR interacting proteins
associated with AT2 R, include AT2 R-interacting protein (ATIP) (also
known as mitochondrial tumor suppressor gene 1 (MTUS1) and
AT2 R binding protein of 50 kDa (ATBP50)) is involved in transinactivation of receptor tyrosine kinases and growth inhibition [105].
The biology and regulation of Ang receptors has been extensively
reviewed [90,101].
3. Beyond the classical RAS
Until recently, the RAS was considered a linear process (Fig. 1)
and Ang II was accepted as the major effector peptide [143]. However the conventional view of the RAS has undergone signicant
change at four main levels: (1) identication of renin/prorenin
receptor, (2) recognition of functionally active Ang II-derived peptides, (3) intracellular RAS and (4) existence of a tissue RAS. The
present review highlights some of these new paradigms focusing
on the tissue system, specically the vascular RAS.
3.1. Renin/prorenin receptor
Renin was considered to be a protease enzyme responsible
for production of Ang I without any direct biological actions.
However it has now been shown that prorenin and renin
bind to specic (pro)renin receptors ((P)RR) [98,99], which activate signaling molecules, including promyelocytic zinc ngers
(PLZF), protein-phosphatidylinositol-3-kinase (PI3K) and mitogenactivated protein (MAP) kinases (ERK1/2 and p38MAP kinase),
promoting cell growth and brosis, independently of Ang II,
in cardiomyocytes, mesangial cells, podocytes, distal tubular
cells, vascular endothelial cells and VSMCs [27,119]. The exact
(patho)physiological signicance of the (P)RR remains unclear
although it may act as an amplier of tissue RAS.
The (P)RR is a multifunctional receptor that mediates effects
beyond the RAS [65]. A truncated form of the receptor (M8.9), may
be an accessory protein of vacuolar H+ -ATPase (V-ATPase) involved
in non-RAS-related functions [86]. The (P)RR/ATP6AP2 is essential for vacuolar H+ -ATPase assembly in cardiomyocytes [3,71].
V-ATPase plays a role in physiological and biochemical processes by
regulating intracellular pH, an effect that is enhanced by (pro)renin
binding to (P)RR [23]. The (P)RR also acts as an adaptor protein
between V-ATPase and Wnt receptors and signals through Wnt in
a (pro)renin-independent manner [23]. Wnt signaling is involved
in cell proliferation, polarity, and fate determination during embryonic development and tissue homeostasis and has been implicated
in various pathologies including cancer.
3.2. ACE2, Ang-(1-7), Ang III, Ang IV and other Ang-derived
peptides
A homologue of ACE, ACE2 catalyzes Ang I and Ang II to generate the Ang peptides Ang-(1-9) and Ang-(1-7), which mediate,
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Angiotensinogen
Renin
Bradykinin
Angiotensin I
ACE
ACE2
Inactive
metabolites
Vasodilati
dil tion
Angiotensin II
AT1R
Angiotensin-(1-7)
Mas
AT2R
Vasoconstriction
Fibrosis
Hypertrophy
Inflammation
Vasodilation
Anti-fibrotic
Anti-growth
Anti-inflammatory
Fig. 1. The classical reninangiotensin system. Kidney-derived renin is secreted into the circulation where it cleaves liver-derived angiotensinogen to angiotensin I, which
is hydrolyzed to angiotensin II (Ang II) by angiotensin converting enzyme (ACE). ACE metabolizes bradykinin to inactive metabolites. A homologue of ACE, ACE2, catalyzes
Ang II to Ang-(1-7). Ang II binds to Ang II type 1 receptors (AT1 R) and Ang II type 2 receptors (AT2 R) on vascular cells, mediating vascular effects. Ang-(1-7) binds to receptor
Mas and induces effects similar to those mediated by AT2 R.
in general, opposite effects to those of Ang II [28,42]. Ang-(17) is metabolized by ACE to Ang-(1-5). Ang-(1-7) is present in
the circulation and in tissues (brain, heart, kidneys, vessels, liver,
reproductive organs) [52,125], and binds to its G protein-coupled
receptor Mas [126].
Other small peptides derived from Ang II include Ang III and Ang
IV. Ang III, formed from Ang II by aminopeptidase A, is a biologically active peptide with actions similar to those of Ang II [8]. Ang
III infusion in experimental models and in humans increases BP,
promotes vasoconstriction and stimulates aldosterone production
[107]. In vitro, it stimulates growth, production of proinammatory
mediators and deposition of extracellular matrix proteins [158].
Ang III binds to AT1 R, as well as to AT2 R. Ang IV is generated from
Ang III by aminopeptidase N and directly from Ang II by the enzyme
d-aminopeptidase. Ang IV increases renal blood ow, it induces
vasodilation and improves cardiac function [165]. Ang IV also exerts
a wide range of neural effects including the ability to enhance
learning and memory recall, anticonvulsant and anti-epileptogenic
properties and protection against cerebral ischemia. Some of these
actions are mediated via the AT1 R, but others are due to binding
to a specic binding site, AT4 R, identied as the transmembrane
enzyme insulin-regulated aminopeptidase (IRAP) [80]. Exact mechanism(s) of action whereby Ang IV induces effects via IRAP are
unclear and the biological signicance of Ang IV/IRAP remains to
be elucidated.
Other Ang peptides include Ang-(3-7), important in the brain
and kidney [44], Ang-(1-9), which enhances bradykinin actions, NO
production, and platelet regulation [100] and Ang-(1-12), implicated in cardiac function [25].
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Heart
Vessels
Adipose
tissue
Kidney
Brain
Tissue
RAS
Immune cells
Gastrointestinal
tract
Hematopoietic
tissue
Endocrine
Tissue
Reproductive
tissue
Liver
Pancreas,
Adrenal, pituitary
Fig. 2. Tissue reninangiotensin systems. Components of the reninangiotensin system are expressed in multiple organs and tissues, some of which are directly involved
in cardiovascular regulation (e.g. heart, vessels and kidneys) and others which are unrelated to cardiovascular control (e.g. Reproductive tissue, pancreas, gastrointestinal
system).
In addition to classical RAS components being identied in vessels, new members of the RAS have been detected, including ACE2,
Ang-(1-7) and Mas. Vascular ACE2 is functionally active and generates Ang-(1-7) from Ang II. Ang-(1-7) is found in the endothelium
and vascular wall [32,136,161] and immunohistochemical staining shows abundant presence in aortic perivascular adventitial
tissue (PVAT) [78,79]. Ang-(1-7), by binding to receptor Mas on
endothelial cells, opposes Ang II actions by mediating vasodilation,
growth-inhibition, anti-inammatory responses, antiarrhythmogenic and antithrombotic effects [123,124] through NOS-derived
NO production, activation of protein tyrosine phosphatases,
reduced MAPK activation and inhibition of NADPH oxidase-derived
generation of reactive oxygen species (ROS) [123,124]. Overexpression of ACE2 in the vascular wall of SHR is associated with improved
endothelial function and attenuated development of hypertension
[117]. Ang-(1-7)-Mas can hetero-oligomerize with AT1 R, thereby
inhibiting Ang II actions. The ACE2-Ang-(1-7)-Mas axis is now considered as a counter-regulatory system to the ACE-Ang II-AT1 R axis
in the vasculature [113], although some evidence indicates that
Ang-(1-7) may also promote brosis and inammation in certain
conditions [40,156].
ProAng-12, a recently characterized metabolite of angiotensinogen, is the newest functional peptide of the RAS to be identied.
It might serve as an alternate substrate for local Ang production
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Fig. 3. Vascular reninangiotensin system. All components of the RAS are present in vascular cells. The expression of vascular renin is very low and probably derives primarily
from circulating renin, which is taken up from the circulation through (pro)renin receptors. Membrane-associated angiotensin converting enzyme (ACE) hydrolyzes Ang I
to Ang II, both in the extracellular and in the intracellular milieu. Vascular ACE2 catalyzes Ang II to Ang-(1-7). Ang II and Ang-(1-7) bind to their respective receptors. Ang II
may also be generated from renin-independent processes involving ProAng-12.
Fig. 4. The adipocyte reninangiotensin system in perivascular adventitial tissue (PVAT) inuences vascular function and contributes to the vascular reninangiotensin
system. Adipocyte-derived Ang II, Ang-(1-7) and aldosterone inuence vascular function through specic vascular smooth muscle cell (VSMC) receptors. Production of
adipocytokines in response to locally generated Ang II may also impact vascular function. Adipocyte-derived renin may be taken up by vascular cells to stimulate production
of Ang II within vascular cells. AT1 R, Ang II type 1 receptor; MR, mineralocorticoid receptor.
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decient in monocytes/macrophages [29], fail to develop hypertension, endothelial dysfunction, vascular remodeling or vascular
inammation following Ang II infusion. Since macrophages and T
lymphocytes express components of the RAS, it is possible that
immune/inammatory cells may contribute to local Ang II levels
in the vessel wall. Expression (mainly mRNA) of angiotensinogen,
ACE and AT1 receptors and Ang II protein has been demonstrated
in macrophages, mast cells and lymphocytes [62,94]. Macrophages
are an important source of thymic renin and Ang II in rats [163].
Upregulation of the RAS in macrophages and immune cells may be
particularly important in conditions associated with vascular injury
and inammation, such as in diabetes, atherosclerosis and hypertension. It should be stressed that these data derive predominantly
from experimental models and the signicance in humans remains
unclear.
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Conicts of interest
10. Conclusions
The global RAS comprises a dual system: circulating RAS and
tissue RAS [69,108,116]. The vascular autocrine/paracrine RAS
may function primarily in controlling vascular tone, whereas the
endocrine circulating RAS may be more important in regulating
short-term cardiovascular-renal homeostasis. All tissues important
in cardiovascular regulation, as well as tissues unrelated to blood
pressure control, e.g. pancreas and gut, possess a local RAS. Exact
functions of the local RAS are unclear but probably contribute to
regional tissue control. Functionally tissue-based RAS may amplify
actions of circulating Ang II. Most components of the RAS, including angiotensinogen, ACE, Ang I and Ang II are expressed in the
vascular system. However it still remains elusive as to whether
renin is synthesized in the vessel wall or whether it is taken up as
kidney-derived renin from the circulation. There have been three
major developments in the eld of the vascular RAS that need to
be highlighted: (1) the ndings that in addition to the classical
components of the RAS, (P)RR, novel Ang peptides and ACE2 are
present in the vessel wall, (2) cells of the immune/inammatory
system may contribute to Ang II in the vessel wall, and (3) activation of the RAS in perivascular adipose tissue may contribute
to the vascular RAS and inuence vascular function. Interventions
targeting both the systemic and the vascular RAS should facilitate
more complete inhibition of the RAS, which in the clinical setting
None.
Acknowledgements
Work from the authors laboratory was supported by grants
44018 and 57886, both from the Canadian Institutes of Health
Research (CIHR). RMT is supported through a Canada Research
Chair/Canadian Foundation for Innovation award. CAN is supported
through a fellowship from the CIHR.
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