Emerging Evidence for a Functional Angiotensin-Converting Enzyme
2-Angiotensin-(1-7)-Mas Receptor Axis : More Than Regulation of Blood Pressure?
Mark C. Chappell
Hypertension. 2007;50:596-599; originally published online September 4, 2007;
doi: 10.1161/HYPERTENSIONAHA.106.076216
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Hypertension Highlights
Emerging Evidence for a Functional Angiotensin-Converting
Enzyme 2-Angiotensin-(1-7)-Mas Receptor Axis
More Than Regulation of Blood Pressure?
Mark C. Chappell
F
rom the initial description of renin activity over a century
ago, the ongoing study of the renin-angiotensin (Ang)aldosterone system (RAAS) continues to yield unexpected
findings that redefine the functional nature of this system, as
well as our concepts on the mechanisms of cardiovascular
regulation. The functional arc of the RAAS can no longer be
viewed solely in terms of increasing blood pressure and
inducing vasoconstriction, although these still remain the
dominant aspects of at least the angiotensin II receptor
subtype 1 (AT1R) pathway. There is clearly compelling
evidence that other components of the RAAS may buffer
actions, because the Ang II-AT2 receptor pathway uses the
identical ligand coupled to a different receptor subtype to
evoke, in many cases, actions that oppose AT1 activation1 (for
a more extensive review). Moreover, parallel pathways
within the RAAS result in novel products distinct from Ang
II that require additional “Ang”-converting enzymes (ACEs)
and unique receptors for these products. Indeed, the recent
discoveries of ACE2, the Ang-(1-7) [AT(1-7)] receptor, and
Ang-(1-12)2 as a potentially new precursor add significant
impetus to revise the RAAS as multiple systems that may
amplify or oppose one another (see the Figure). In this brief
review, the current evidence for the physiological relevance
of these new components of the RAAS is assessed.
Kidney
Half a century after the discovery of ACE, a new homolog of
the enzyme termed “ACE2” was identified. Ang I was indeed
a substrate for the enzyme, but the product was the nonapeptide Ang-(1-9) and not Ang II. Subsequent studies find that
the conversion of Ang II to Ang-(1-7) is the preferred
pathway with a 500-fold greater efficiency than that for Ang
I. Consistent with the apical expression of ACE2 in the renal
epithelium, we and others find both tubular and urinary ACE2
activity that converted Ang II to Ang-(1-7) but did not
process Ang I to Ang-(1-9), providing further evidence that
ACE2 is likely the major catalytic path for Ang-(1-7) formation.3–5 The localization of ACE2 in the proximal tubule
epithelium along with other elements of the RAAS (ACE,
angiotensinogen, and Ang receptors) certainly implies a role
for the enzyme in the formation of Ang-(1-7) from Ang II.4
Gurley et al6 developed additional ACE2 knockout models
and, dependent on the background strain, report higher blood
pressure in mice lacking this carboxypeptidase. Moreover,
the relative tissue levels of renal Ang II were significantly
elevated in comparison with wild-type mice, although commensurate measurements of Ang I and Ang-(1-7) were not
performed. Oudit et al7 in their ACE2 knockout model found
that these older mice exhibit a greater degree of glomerulosclerosis and proteinuria, which was attenuated by AT1
receptor blockade. Interestingly, the kidneys of the female
ACE2 knockout mice did not reveal evidence of injury and
were apparently protected from the loss of the enzyme.
Diabetic nephropathy is clearly influenced by an activated
RAAS, and both ACE inhibitors and AT1 receptor antagonists
are effective in attenuating the progression of injury. Renal
ACE2 is reduced in the proximal tubules of the
streptozotocin-induced model of type 1 diabetes, and the
attenuation of renal injury by ACE inhibition is associated
with increased ACE2 expression.8 In turn, chronic ACE2
inhibition in the diabetic db/db mice exacerbates the extent of
albuminuria ⬇3-fold.9 Although Ang content was not measured, the db/db mice exhibited increased glomerular expression of ACE and reduced ACE2 as compared with the control
db/dm mice. Interestingly, the localization studies revealed
distinct patterns of staining for ACE2 and ACE within the
glomerulus: ACE2 in podocytes and ACE in the endothelial
cells.9 In this regard, Ang-(1-7) or its receptor agonist Aventis
(AVE) 0991 attenuates proteinuria and improves renal vascular activity in the diabetic rat but did not reverse the urinary
excretion of lysozyme, a marker of tubulointerstitial damage.10 In addition, the ratio of Ang-(1-7) to Ang II formed
from Ang I was lower in glomeruli isolated from the kidneys
of diabetic rats.11 Thus, a reduction in the renal expression of
Ang-(1-7) in diabetes may exacerbate renal injury. These
studies also suggest that the glomerulus may be a second key
site within the kidney where ACE2 may influence the local
expression of Ang peptides and renal function. Ang-(1-7)
abrogates the Ang II-dependent activation of mitogen-activated protein (MAP) kinase in primary cultures of proximal
Received April 25, 2007; first decision May 16, 2007; revision accepted August 6, 2007.
From the Hypertension and Vascular Disease Center, Wake Forest University School of Medicine, Winston-Salem, NC.
Correspondence to Mark C. Chappell, Hypertension and Vascular Disease Center, Wake Forest School of Medicine, Medical Center Boulevard,
Winston-Salem, NC 27015. E-mail [email protected]
(Hypertension. 2007;50:596-599.)
© 2007 American Heart Association, Inc.
Hypertension is available at http://hyper.ahajournals.org
DOI: 10.1161/HYPERTENSIONAHA.106.076216
596
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Chappell
ACE2 and Ang-(1-7)
597
Figure. Cascade of the processing of angiotensin peptides and their interaction with AT1 and AT(1-7) receptor systems. ACE cleaves Ang
I, releasing the dipeptide His-Leu to form Ang II, and ACE2 subsequently hydrolyzes Ang II to Ang-(1-7). ACE also metabolizes Ang(1-7) to Ang-(1-5) and the dipeptide His-Pro. Ang-(1-12) may be cleaved from angiotensinogen (Aogen) and potentially processed (---⬎)
directly to Ang II or Ang-(1-7). Ang-(1-7) may attenuate the inflammatory and fibrotic actions of the Ang II-AT1 receptor pathway
through inhibition (-) of the MAP kinase kinase (MAPKK) pathway, the potential stimulation (⫹) of cellular phosphatases, the inhibition of
cyclooxygenase-2 (COX2) and other proinflammatory agents, as well as the stimulation of NO. Although not shown, the AT2 and bradykinin receptor systems may interact with these pathways as well.
tubule epithelial cells (Figure).12 Moreover, the inhibitory
actions of Ang-(1-7) were blocked by the Ang-(1-7) antagonist (D-Ala7)-Ang-(1-7) consistent with the immunocytochemical evidence for the AT(1-7)-Mas receptor in the tubular
epithelium.4
Heart and Vasculature
In the spontaneously hypertensive rat (SHR) heart, lentiviral
expression of ACE2 has amelioratory effects on blood pressure and cardiac fibrosis, although the circulating or cardiac
content of Ang II and Ang-(1-7) was not assessed.13 These
findings, however, are important in demonstrating that overexpression of ACE2 can effectively alter the balance of the
RAAS in this hypertensive model. Pan et al14 find that, in a
porcine pacing model, cardiac ACE2 is markedly reduced,
whereas ACE is increased. Tallant et al15 report that Ang(1-7) inhibits the growth of cardiomyocytes and is associated
with reduced activity of MAP kinase, responses that are
opposite those for Ang II-AT1 activation. The growth inhibition and reduction in MAP kinase activity were blocked by
the downregulation of the AT(1-7)-Mas receptor using antisense nucleotides against the receptor. Ang-(1-7)-dependent
growth inhibition was also blocked by the AT1-7R antagonist
(D-Ala7)-Ang-(1-7) but not by AT1 or AT2 antagonists.
Recent studies from this group demonstrate that Ang-(1-7)
reduces adenocarcinoma growth in vivo potentially through
the reduction in the cyclooxygenase-2/proinflammatory pathway.16 Indeed, the antiproliferative actions of Ang-(1-7) may
explain the clinical observation that ACE inhibitor therapy is
associated with a reduced incidence of certain types of
cancer. Preliminary studies also reveal that Ang-(1-7) inhibits
cyclooxygenase-2 expression in cardiofibroblasts.17 Indeed,
the anti-inflammatory actions of Ang-(1-7) may underlie the
ability of the peptide to reverse cardiac fibrosis in the
DOCA-salt rat model.18 In this case, the antifibrotic actions of
Ang-(1-7) were independent of a reduction in blood pressure.
The ACE2-deficient mice who develop cardiomyopathy also
exhibit evidence of increased oxidative stress and inflammation, as well as MAP kinase and phosphatidylinositol
3-kinase activation.19 Ang-(1-7) reduces collagen formation,
as well as the expression of transforming growth factor-␤,
endothelin-1, and leukemia inhibitory factor in cardiofibroblasts.20 In Ang II-dependent cardiac hypertrophy, Ang-(1-7)
abolished the extent of cardiac hypertrophy and interstial
fibrosis without changes in blood pressure.21 Importantly, the
coadministration of the (D-Ala7)-Ang-(1-7) reversed the cardioprotective effects of Ang-(1-7). Santos et al22 report
impaired cardiac function in the Mas-deficient mouse that
was associated with increased forms of collagen and fibronectin. Moreover, Ang-(1-7) or AVE 0991 provide comparable cardioprotection from induced ischemia in diabetic
rats, although the extent of hyperglycemia was not attenuated.10 Similar protective actions of Ang-(1-7) and AVE 0991
were also observed in the NG-nitro-L-arginine methyl ester–
treated spontaneously hypertensive rat.23 Sampaio et al24 find
that Ang-(1-7) evokes phosphorylation of the serine-1177 and
dephosphorylation of threonine-495 residues to activate endothelial NO synthase in human endothelial cells. Because
Ang-(1-7) does not evoke an increase in intracellular calcium,
these investigators implicate the AKT/phosphatidylinositol
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598
Hypertension
October 2007
3-kinase pathway in endothelial NO synthase activation.
Indeed, the heptapeptide stimulated phosphorylation of AKT,
of which the downstream substrate is endothelial NO synthase (Figure). Similar results on endothelial NO synthase
activation and NO release were observed in the Mas–
transfected but not control Chinese hamster ovary cells,
further substantiating the role of the Mas receptor mediating
the Ang-(1-7)– dependent activation of endothelial NO synthase. Although, these studies clearly elevate the relevance of
an Ang-(1-7)-Mas pathway by demonstrating a functional
pathway in human cells, the acute vasodilatory effects of the
peptide have not been demonstrated in vivo.25 However, one
should not discount that Ang-(1-7) lacks any effect in humans
(normotensive or hypertensive), because the reliance on
blood pressure or flow may hinder our view to other potential
actions of the peptide.
Brain
The brain is also a key area for cardiovascular regulation
containing multiple RAAS components, if not a complete
system. Doobay et al26 find ACE2 mRNA and protein
expression in the mouse brain, specifically in cardiovascular
relevant areas, such as the subfornical organ, area postrema,
paraventricular nucleus, and ventrolateral medulla. ACE2
expression was exclusively relegated to neurons; however,
the staining was predominantly cytoplasmic, which is surprising given that the enzyme is primarily a membrane-anchored
protein with the catalytic domain facing the extracellular
surface. The processing pathways for the brain RAAS remain
equivocal, but perhaps the cytosolic location of ACE2 may
indicate a unique mechanism for the neuronal expression
and/or regulation of intracellular Ang II and Ang-(1-7).
Yamazato et al27 report that ACE2 expression in the rostral
area of the ventrolateral medulla was lower in the SHR versus
normotensive controls, which is consistent with reduced renal
content in this hypertensive model. Most interestingly, the
overexpression of ACE2 in this area reduced both blood
pressure and heart rate in the SHR. Additional studies are
required to determine the exact mechanisms for the blood
pressure–lowering actions of ACE2; however, Ang-(1-7) is
known to elicit cardiovascular actions in this area. Sakima et
al28 find that the reduced control of heart rate in older rats is
associated with the loss of an Ang-(1-7) effect in the nucleus
tractus solitarius. Preliminary findings by Diz et al29 reveal
that ACE2 inhibition within the nucleus tractus solitarius
impairs the baroreflex to a similar extent as the Ang-(1-7)
antagonist and clearly support a functional role for ACE2 in
this region.
Conclusion
Evidence that ACE2 directly forms Ang-(1-7) and for a
distinct Ang-(1-7) receptor has stimulated resurgence in
experimental studies resulting in a wider re-examination of
Ang-(1-7). Additional interest, apart from the functional
aspects, lies in elucidating the complex regulation of these
components within the RAAS. Ang II directly downregulates
ACE2 through activation of the AT1 receptor30 consistent
with studies in the intact animal that ACE or AT1 blockade
increases ACE2 expression.4 Although Ang-(1-7) alone did
not influence the basal expression of ACE2 in the cell
experiments, the peptide attenuated the inhibitory effects of
Ang II on ACE2 via a receptor-dependent mechanism.
Current evidence suggests that aldosterone downregulates
ACE2,31,32 whereas the mineralocorticoid is known to increase the expression of ACE, AT1 receptors, and intrarenal
Ang II.33 The downregulation of ACE2 leading to higher Ang
II may potentially be compensated by AT2 receptor binding of
Ang II. In turn, either ACE inhibition or AT1 blockade may
promote ACE2-dependent formation of Ang-(1-7) and its
receptor-associated pathways. Indeed, the relationship between the AT2 and Ang-(1-7) cellular pathways is an area
requiring further study. Finally, the demonstration of endogenous Ang-(1-12) in the rat may portend renin-independent
pathways that culminate in the formation of biologically
active peptides.2 The peptide bond Tyr12-Tyr13 hydrolyzed to
yield Ang-(1-12) from rat angiotensinogen is structurally
distinct from the Leu10-Leu11 bond recognized by rat renin to
form Ang I. Moreover, these bonds are also distinct for
human angiotensinogen. Although the Ang-(1-12) peptide
may not exhibit any functional action, the processing to this
intermediate peptide may convey an additional level of
regulation within the RAAS (Figure). Since this research on
Ang-(1-7) originated by my colleagues at the Cleveland
Clinic began 18 years ago, one could scarcely envisage the
expansion of the RAAS that has occurred. There is little
doubt that studies in the next few years will resolve the
relevance of an endogenous Ang-(1-7)-ACE2-Mas pathway,
particularly its role in tissue injury, inflammation, and cellular growth, and perhaps reveal whether this pathway is of
therapeutic value. In this regard, the orally active agonist
AVE 0991 or the development of related compounds may
provide additional cardiovascular benefits.
Sources of Funding
These studies were supported by the National Institutes of
Health grants (HL-56973, HL-51952, HD047584, and
HD017644) and the American Heart Association (grants
AHA-151521 and AHA-355741).
Disclosures
None.
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