Review
Pathophysiological Role of Angiotensin II Type 2 Receptor
in Cardiovascular and Renal Diseases
Hiroaki Matsubara
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Abstract—Since the discovery of nonpeptidic ligands, the receptors for angiotensin (Ang) II have been classified into 2 subtypes
(Ang II type 1 receptor [AT1-R] and Ang II type 2 receptor [AT2-R]). AT1-R mediates most of the cardiovascular actions of
Ang II. AT2-R is expressed at very high levels in the developing fetus. Its expression is very low in the cardiovascular system
of the adult. The expression of AT2-R can be modulated by pathological states associated with tissue remodeling or
inflammation. In failing hearts or neointima formation after vascular injury, AT2-R is reexpressed in cells proliferating in
interstitial regions or neointima and exerts an inhibitory effect on Ang II-induced mitogen signals or synthesis of extracellular
matrix proteins, resulting in attenuation of the tissue remodeling. An extreme form of cell growth inhibition ends in
programmed cell death, and this process, which is initiated by the withdrawal of growth factors, is also enhanced by AT2-R.
Cardiac myocyte- or vascular smooth muscle–specific mice that overexpress AT2-R display an inhibition of Ang II-induced
chronotropic or pressor actions, suggesting the role of AT2-R on the activity of cardiac pacemaker cells and the maintenance
of vascular resistance. AT2-R also activates the kinin/nitric oxide/cGMP system in the cardiovascular and renal systems,
resulting in AT2-R–mediated cardioprotection, vasodilation, and pressure natriuresis. These effects, transmitted by AT2-R, are
mainly exerted by stimulation of protein tyrosine or serine/threonine phosphatases in a Gi protein–dependent manner. The
expression level of AT2-R is much higher in human hearts than in rodent hearts, and the AT2-R–mediated actions are likely
enhanced, especially by clinical application of AT1-R antagonists. Thus, in this review, the regulation of AT2-R expression,
its cellular localization, its pathological role in cardiovascular and kidney diseases, and pharmacotherapeutic effects of AT2-R
stimulation are discussed. (Circ Res. 1998;83:1182-1191.)
Key Words: angiotensin II receptor n angiotensin II type 2 receptor n angiotensin II AT2 receptor n angiotensin II
type 1 receptor n angiotensin II AT1 receptor
T
he biological effects caused by circulating angiotensin
(Ang) II are diverse, widespread, and play a critical role
in the regulation of the cardiovascular and renal systems
(Figure 1). The components of the renin-angiotensin system
are present in peripheral tissues such as vasculature, kidneys,
adrenal glands, and hearts, all of which locally produce Ang
II.1 Ang II produced in the peripheral tissues binds to specific
receptors through the autocrine or paracrine system and
exerts growth-promoting effects on the tissue remodeling
process.2 The well-known Ang II actions such as the regulation of blood pressure and water-electrolyte balance have
been attributed mainly to the activation of various signaltransduction pathways modulated by Ang II type 1 receptor
(AT1-R). However, the discovery of highly selective, peptidic, and nonpeptidic ligands such as CGP42112A and
PD123319 has led to the identification of a second subtype
(Ang II type 2 receptor [AT2-R].3–7 This receptor is expressed
at very high levels in the developing fetus. By contrast, in the
adult, its expression is restricted to the adrenals, uterus,
ovary, heart, and specialized nuclei in the brain. Initially, the
cDNA for AT2-R was isolated by expression cloning from
PC12 cells8 and whole fetus.9 Knockout mice for the AT2-R
gene were developed, and studies of these mice suggested
that AT2-R has a physiological role in blood pressure control
and emotional instability and fearfulness.10,11 In addition, an
AT2-R–mediated inhibitory effect on the growth-promoting
signals has been found.5,6 Treatment with AT1-R antagonists
causes a marked elevation of levels of plasma Ang II, which
selectively binds to AT2-R and exerts as yet undefined
effects.12 Thus, elucidation and understanding of AT2-R–
mediated pathological actions have important pharmacotherapeutic implications. This review examines the results of
studies into the structure-function, transcriptional control and
gene expression, signal-transduction mechanism, cellular distribution, and pathophysiological roles of AT2-R as well as
potential issues concerning clinical application of AT1-R
antagonists.
Structural Features of AT2-R
The second isoform of the Ang II receptor, AT2-R, has been defined
as the receptor that binds specifically to CGP42112 and to a series of
Received May 14, 1998; accepted September 23, 1998.
From the Department of Medicine II, Division of Endocrine Hypertension and Metabolism and Nephrology, Kansai Medical University, Moriguchi,
Osaka, Japan.
Correspondence to Hiroaki Matsubara, MD, Department of Medicine II, Kansai Medical University, Fumizonocho 10-15, Moriguchi, Osaka 570-8507,
Japan. E-mail [email protected]
© 1998 American Heart Association, Inc.
Circulation Research is available at http://www.circesaha.org
1182
Matsubara
December 14/28, 1998
1183
the Arg1082 in extracellular loop, and the Asp297 in extracellular
loop 3 play an important role in Ang II binding to AT1a-R, whereas
mutations of Arg182 and Asp297, but not Tyr108, drastically
impaired Ang II binding to AT2-R.15 The AT2-R gene has been
characterized in both the mouse16,17 and human.18 –20 It exists as a
single copy localized on the X chromosome in both species and
contains no intron in its coding region. This excludes the possibility
of multiple forms of AT2-R encoded by several homologous genes or
delivered by alternative splicing. Genomic Southern blot analyses
also have indicated that there are no other subtypes to the AT2-R
gene family, such as AT1a-R or AT1b-R, found in the AT1-R family.8,9
Regulation of AT2-R Gene Transcription
and Expression
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Figure 1. Proposed AT2-R–mediated effects on cardiovascular
and renal system. PP2A indicates serin/threonine phosphatase
2A; Ik, delayed rectifier K1 current; IA, transient outward K1 current; Ca21/CaMK; calcium calmodulin kinase; MLCK, myosin
light chain kinase; and EDHF, endothelium-derived hyperpolarizing factor.
PD compounds.4 Its abundance in mesenchymal tissues of the
developing fetus, such as the uterus, the adrenal medulla, pheochromocytoma, and specific brain regions suggested neuronal and developmental roles for AT2-R.3–7,13,14 This receptor had been thought not
to be a seven-transmembrane receptor, given that its ligand binding
affinity was not reduced by stable GTP analogues, and it did not
show agonist-induced internalization.3,5 The cDNA isolated from
PC12 cells8 or rat fetus9 by expression cloning encoded a protein
with a 363 amino-acid residue, which corresponded to a theoretical
molecular weight of 41 303, and it showed a seven-transmembrane
domain receptor that included the highly conserved sequence
Asp141-Arg142-Tyr143 in the N-terminal region of the second
cytosolic loop and the conservation of residues known to be crucial
for binding in other G protein– coupled receptors. However, it shared
only a 32% amino-acid sequence identity with AT1a-R. Mutational
analysis of AT1a-R indicated that the Tyr108 in extracellular loop 1,
TABLE 1.
The gene expression of AT2-R is regulated by multiple factors (Table
1). Increase in intracellular CA21 levels by Ca21 ionophore and
activation of protein kinase C (PKC) by phorbol ester markedly
downregulated the AT2-R mRNA level in PC12 cells.21 Norepinephrine and Ang II (via AT1-R), which elevate Ca21 levels and activate
PKC, downregulate the AT2-R expression in cardiac myocytes.22
Growth factors (epidermal growth factor, nerve growth factor, and
platelet-derived growth factor) also downregulate AT2-R expression
in PC12 cells,22,23 R3T3 cells,24,25 and vascular smooth muscle cells
(VSMCs).26 Stimulation of growth factor receptors results in the
formation of an activator protein AP-1 complex including Fos and
Jun transcription factors, which in turn binds to the AP-1 site of the
promoter region of many genes. This effect is mimicked by PKC
activation with phorbol ester. Considering that both growth factors
and phorbol ester suppress the AT2-R mRNA expression, their
effects may converge on the AP-1 site. In agreement with this
hypothesis, the AP-1 site was shown to be present in the promoter
region of rat AT2-R,23 and AT2-R gene transcription assessed by
nuclear runoff assays is inhibited by growth factors and phorbol
ester.22 The promoter region of the AT2-R gene possesses a glucocorticoid response element, CAAT/enhancer-binding protein, nuclear
factor-interleukin 6, AP-1, and a cAMP response element, suggesting a transcriptional regulation by glucocorticoids, cytokines, phorbol esters, and cAMP.23,27 Interestingly, the inhibition of AT2-R
expression by glucocorticoid or cAMP analogues is regulated at the
gene transcription level.22,23 Thus, multiple factors downregulate
AT2-R expression. Ichiki et al24,28 and Kambayashi et al29 reported
Pharmacology, Regulation, and Physiological Function of AT1-R and AT2-R
AT1-R
AT2-R
Distribution
Artery, liver, kidney, adrenal gland, heart, brain (glial cell)
Fetus, brain (neuron), myometrium, kidney, lung, heart
Ligand
Losartan, TCV116, valsartan
PD123319, CGP42112A
Amino acid
359
363
Chromosome
No. 3 (human), No. 17 (rat)
X chromosome
Exon
5 (human), 3 (rat)
3 (human, rat)
Signaling
Gq/Gi coupling, PLC activation (Ca21/IP3), Ras/ERK,
JAK2/STATS
Gi coupling, tyrosine phosphatase, serine/threonine
phosphatase, kinin/NO/cGMP
Function
Vasoconstriction, aldosterone secretion, hypertrophy,
cellular growth, catecholamine release
Voltage-gated Ik/Ito K1 channel activation, T-type Ca21 channel
inhibition, growth inhibition, apoptosis induction, vasodilation
Null mice
Anomalous development of renal calyx, decrease in blood
pressure, hypertrophy of renin-producing cell
Increase in basal blood pressure, hyperresponse to Ang II
pressor action, exploratory behavior, anomalous development
of ureter
Cardiac overexpression
Bradycardia and arrhythmia, atrial hyperplasia
Negative chronotropic action, inhibition of AT1-R–mediated ERK
activity
Arterial overexpression
Unestablished
Hyporesponse to Ang II pressor action, decrease in arterial
vascular resistance
Regulation
Upregulation by glucocorticoid, cAMP, cytokines, cardiac
hypertrophy, myocardial infarction
Downregulation by myocardium in failing heart
Downregulation by glucocorticoids, growth factors, phorbol
ester, Ca21 ionophore, Gq-coupled receptor stimulation
Upregulation by insulin, insulin-like growth factor, cytokines,
interstitial region in remodeling heart
1184
Angiotensin II Type 2 Receptor
the upregulation of the AT2-R gene by interleukin (IL)-1b, insulin,
and insulin-like growth factors in R3T3 cells and VSMCs. IL-1b is
one of the important cytokines mediating inflammation, and it may
be involved in AT2-R induction during the process of inflammation.30 Fetal mesenchymal fibroblasts, which highly express AT2-R,
express a substantial amount of insulin-like growth factor-I and its
receptor31; insulin may be important for the abundant expression of
AT2-R in fetal mesenchymal tissues. Although these multiple factors
regulate the expression of AT2-R, the molecular mechanisms responsible for hormonal control and cell-specific expression of the AT2-R
gene are less defined than those for control and expression of the
AT1a-R gene.32–35 Expression of the AT2-R gene is dependent on
growth state. When PC12 cells,22 R3T3 cells,36,37 or mesangial
cells38 reach a confluent quiescent state, AT2-R expression is
increased markedly. This gene regulation is exerted at the transcriptional level.22,23 Horiuchi et al36,37 demonstrated that interferon
regulatory factor-1, the expression of which is increased during
confluent state and by serum depletion, binds to the interferon
regulatory factory-binding motif of the AT2-R gene promoter region
and upregulates its gene transcription.
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AT2-R–Mediated Effects on Ang II–Induced
Mitogen Signaling, Apoptosis, Kinin/Nitric
Oxide/cGMP System
Involvement of Phosphotyrosine Phosphatase
In contrast with AT1-R, the AT2-R–mediated signaling mechanism is
not well established. Before the structure of AT2-R had been
determined, numerous studies attempted to elucidate signal transduction pathways associated with this subtype. Cell lines such as
PC12W cells, neuroblastoma (NG108-15, NIE-115), or fibroblasts
(R3T3) expressing only AT2-R were used as models for signaling
studies. In the PC12W and NIE-115 cells, AT2-R activates phosphotyrosine phosphatase (PTP) to inhibit cell proliferation39,40 and
differentiation.41 In NIH3T3 cells stably expressing AT2-R, Ozawa et
al42 also found the AT2-R–mediated inhibitory effect on serumstimulated cell growth in a pertussis toxin-sensitive manner. Using a
membrane-associated fraction in the postnuclear fraction isolated
form R3T3 cells, Tsuzuki et al43,44 reported that AT2-R stimulation
caused activation of PTP when both nitrophenylphosphate and the
peptide substrate Raytide containing a phosphotyrosine residue were
used as targets. They also described the suppression of growth
stimulation of R3T3 fibroblasts by basic fibroblast growth factor.
This suppression correlated dose-dependently with AT2-R–mediated
signals, suggesting the role of PTP in AT2-R–mediated inhibition of
cellular growth.43
Inhibition of AT1-R–Mediated Extracellular
Signal-Regulated Kinase Activation
In cells expressing AT1-R, Ang II activates extracellular signalregulated kinase (ERK), which leads to a mitogenic or hypertrophic
response through activation of tyrosine kinase system.45,46 With use
of coronary endothelial cells expressing both AT1-R and AT2-R47 or
an overexpression model of AT2-R in VSMC,48 AT2-R was shown to
have an inhibitory effect on AT1-R–mediated growth-promoting
action assessed by DNA synthesis, and in the latter experiment,
AT2-R decreased the AT1-R–mediated ERK activity. Janiak et al49
reported the selective activation of AT2-R as an effective approach
for the suppression of neointima formation after balloon catheterization. AT2-R stimulation inhibits AT1-R–mediated DNA and cell
growth in myocytes50 or fibroblasts51,52 isolated from neonatal rat
hearts and in cardiac fibroblasts from myopathic hamsters.52 The
inhibition of DNA synthesis by AT2-R was also reported in zona
glomerulosa cells from rat adrenal glands.53 Furthermore, Masaki et
al54 ascertained that AT2-R significantly inhibits AT1-R–mediated
ERK activation in perfused mouse hearts overexpressing AT2-R. The
AT2-R–mediated antiproliferative effect on DNA synthesis also was
demonstrated in embryonic renomedullary interstitial cells.55 The
mechanism of AT2-R participation in this process might be associated with reduced ERK activity caused by the activation of ERK
phosphatase 1 (MKP-1), a dual-specificity phosphatase that acts on
both phosphotyrosine and phosphothreonine. Horiuchi et al56 reported that AT2-R stimulation dephosphorylates Bcl-2 by activating
MKP-1 and induces apoptosis in PC12W cells. Bedecs et al57
reported that AT2-R–mediated inhibition of serum- or growth factorinduced ERK activity in NIE-115 cells is associated with vanadatesensitive PTP, in which catalytic activity of Src homology 2 domain
phosphatase-1 (SHP-1), a soluble PTP, is an early transducer of the
AT2-R signaling pathway. These investigators also found that expression of MKP-1 is not modified by AT2-R.57 In neuronal cultures
isolated from neonatal rat hypothalamus or in nondifferentiated
NG108-15 cells (neuroblastoma cells), activation of AT2-R reportedly elicits stimulation of outward58,59 and delayed rectifier K1
currents60 and inhibits T-type Ca21 current.61 These effects in
neuronal cultures appear to be due to activation of serine/threonine
phosphatase mediated in a Gi protein– dependent manner. In contrast, in neuroblastoma (NIE-115) AT2-R reportedly induces a
marked decrease in phosphorylation of several cellular proteins on
tyrosine residues.62 Bottari et al63 and Brechler et al64 reported that
AT2-R stimulation causes activation of a membrane-associated PTP
and inhibition of atrial natriuretic peptide-sensitive particular guanylate cyclase via a G protein–independent pathway. These studies
show that AT2-R inactivates ERK and that ERK activity can be used
as a sensitive index of AT2-R action, rather than used to directly
determine PTP activity, which is difficult because of the high
background contribution of several PTPs.5
AT2-R–Mediated Induction of Apoptosis
An extreme way of cell growth inhibition might direct cells into
programmed cell death. AT2-R has been associated with apoptotic
changes in rat ovarian granulosa cells in culture.65 Prolonged serum
depletion, which is enhanced by Ang II treatment, elicits programmed cell death of R3T3 cells.66 PC12W cells also undergo
apoptosis upon depletion of nerve growth factor, which also is
enhanced by Ang II, and this effect was attenuated by inhibition of
MKP-1 function and by the PTP inhibitor orthovanadate.66 Horiuchi
et al56 reported that ERK plays a critical role in inhibiting apoptosis
in PC12W cells by phosphorylating Bcl-2 and that AT2-R inhibits
ERK activation, resulting in the inactivation of Bcl-2 and the
induction of apoptosis. Hayashida et al67 showed that a synthetic
peptide containing a 22-residue sequence from the third cytosolic
loop of rat AT2-R suppresses the ERK activity when transferred into
VSMCs, and that this inhibition is reversed by pertussis toxin or
orthovanadate, suggesting that the third cytosolic loop of AT2-R
plays a role in the activation of a Gi-mediated PTP that inhibits ERK.
Zhang and Pratt68 also reported the direct binding of AT2-R to
immunoprecipitated Gia2 and Gia3 proteins. In contrast, Cigola et al69
reported that the stimulation of AT1-R but not AT2-R induces
apoptosis by Ca21-dependent endonuclease in neonatal rat myocytes.
No apoptotic changes were observed in cardiac myocytes from
transgenic mice expressing AT2-R specifically in the heart.54
Involvement of Bradykinin/Nitric
Oxide/cGMP Systems
AT2-R–mediated activation of the kinin and nitric oxide (NO) system
has been reported in bovine endothelial cells,70 isolated rat carotid
arteries,71 canine microvessels from coronary arteries,72 rat aortic
strips,73 rat kidney,74 and rat heart.75 In a rat model of heart failure
due to myocardial infarction,75 the reduced cardiac function and
cardiac fibrosis were improved by an AT2-R antagonist as well as by
a bradykinin receptor antagonist. In stroke-prone spontaneously
hypertensive rats,76 aortic cGMP production stimulated by Ang II
infusion was inhibited by an AT2-R antagonist as well as by a
bradykinin receptor antagonist or NO synthase inhibitor, suggesting
the involvement of bradykinin and NO in the AT2-R signaling.
Siragy et al74 reported using a microdialysis technique that AT2-R
stimulates renal production of cGMP in response to Na depletion,
and that this effect is mediated by NO production.77 AT2-R–mediated
NO production also is involved vitally in AT2-R–mediated pressure
natriuresis an diuresis.78,79
Matsubara
December 14/28, 1998
1185
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Figure 2. Emulsion autoradiography of
Ang II receptors in human failing hearts.
Adjacent sections obtained from a
patient with dilated cardiomyopathy were
stained with hematoxylin-cosin or incubated with 125I-[Sar1,Ile8] Ang II (0.25
nmol/L), dipped in emulsion, developed,
fixed, and then stained with Kernechtrot.
On sections stained with hematoxylineosin (No. 1), the fibrous regions are
indicated by arrows. Adjacent sections
were incubated with 125I-[Sar1,Ile8] Ang II
in the absence of competitors (No. 2,
total Ang II binding) and in the presence
of PD123319 (0.1 mmol/L) (no. 3), losartan (0.1 mmol/L) (No. 4), or Ang II
(3 mmol/L) (No. 5, nonspecific binding).
Binding sites were localized in regions
with interstitial fibrosis, whereas fewer
were seen in the surrounding myocardium. The Ang II binding sites in fibrous
regions were strongly inhibited by
PD123319 (No. 3) but not by losartan
(No. 4). (Figure was previously published
in Tsutsumi et al [Circ Res.
1998;83:1035–1046].)
Expression and Cellular Localization of
AT2-R in the Heart
Inhibition of Ang II production by angiotensin-converting enzyme
(ACE) inhibitors is a major new approach for treatment of hypertension, cardiovascular remodeling, heart failure, and chronic renal
diseases. Both AT1-R and AT2-R have been observed in cardiac
myocytes isolated from neonatal rat hearts.50,80,81 Cardiac fibroblasts
isolated from neonatal and adult rat hearts express abundant amounts
of AT1-R ('8-fold more than that in myocytes)80 but not of
AT2-R.81– 84 Although some attempts to detect the AT2-R in adult
rodent myocytes by a binding assay or polymerase chain reaction
have proved negative,84 – 86 other researchers have obtained positive
results.24,87–90 Although autoradiography results also indicated the
presence of AT2-R protein in the adult rat myocardium,91 an in situ
hybridization study did not detect AT2-R mRNA in cardiac muscle of
adult rat but did show it in the annulus of all valves during the
perinatal period.92 Thus, the proportion of cardiac AT2-R expressed
in situ in the rat heart varies from that detected in cultured cells,93
possibly reflecting downregulation of AT2-R expression after the
isolation of mammalian cells84,94 and the growth-dependent regulation of AT2-R expression in cultured cells.21,66
The expression pattern of AT2-R in the human heart is quite different
from that in the rat heart, and human adult hearts express substantial
amounts of AT2-R. Tsutsumi et al95 found that the amount of Ang II
receptors in human left ventricular tissues was in the range of 3.8 to 17.3
fmol/mg protein, and that the proportion of AT2-R to the total Ang II
binding sites was about 41%. The amount of Ang II receptors is similar
to the amounts reported by others96 –100; however, the proportion of
AT2-R to binding sites differs between these studies. Interestingly,
Tsutsumi et al95 found that AT1-R and AT2-R decreased by as much as
by 3062.7% and 8.261.4%, respectively, during the freezing of tissue
samples. This finding means that great care should be taken to factor in
the experimental conditions when Ang II receptor densities are measured in tissue samples. In addition, Rogg et al101 reported a relatively
high amount of Ang II receptors (118 fmol/mg protein) in the human
atria when they used combined fractions including plasma membranes
and internalized receptors; other investigators96 –100 measured Ang II
receptors using only membrane fractions. In fact, Regitz-Zagrosek et
al97 found that the Ang II receptor densities determined with combined
fractions were increased markedly compared with those found by using
only membranes. Urata et al96 reported that the basal portion of human
left ventricular tissues contained higher densities of Ang II receptors
than those in other portions. Ang II receptor densities are affected by the
methodological differences, such as dissimilarities in the purity of
membrane fractions, the portion of ventricles examined, or membrane
preparation.
Cellular localization of AT2-R in the human heart has been
examined mainly using emulsion autoradiography.95,99,102,103 The expression of cardiac AT2-R was localized more highly in the fibroblasts present in the interstitial regions than those in the myocardium95,99,102 (Figure 2). In contrast, AT1-R is localized most
abundantly in nerves distributed in the myocardium, and its expression level in the myocardium itself or interstitial regions is very
low,95,99,102 although the AT1-R protein might be partially degraded
during sample preparation such as during the freezing of tissues.95
These findings imply that the expression of AT2-R in the heart
increases in parallel with the progression of interstitial fibrosis,
which corresponds to the reports that AT2-R expression in human
hearts increases during cardiac remodeling as a result of dilated
cardiomyopathy or ischemic heart diseases.95,99,102 AT2-R expression
in human hearts also reportedly increases in parallel with intracardiac
filling pressures.103 The results of ligand binding and autoradiographic studies on human heart tissues appear to differ from those
obtained in studies of isolated cardiac cells. Although AT2-R binding
sites are localized in interstitial regions in human hearts in situ,95,99,102 cultured human cardiac fibroblasts display mainly AT1-R–
mediated effects on collagen synthesis.104 Atypical Ang II binding
sites for Ang 1–7 were detected on human cardiac fibroblasts,105,106
whereas Ang 3– 8 binding sites were present on rabbit cardiac
fibroblasts107 or myocardial membranes of guinea pig and rabbit
hearts.108 Two subtypes of the AT1-R, AT1a-R and AT1b-R, were
encoded in human tissues,109 and there was heterogeneity in mammalian AT2-R,110 but these reports are isolated ones, which are not
followed up by confirmation.
Regulation of Cardiac AT2-R Expression
During Cardiac Remodeling
Both AT1-R and AT2-R are upregulated to different extents in
pathological conditions, such as cardiac hypertrophy,87,111–113 an
1186
Angiotensin II Type 2 Receptor
TABLE 2.
Expression of AT1-R and AT2-R in Cardiovascular Diseases
Cardiac hypertrophy
Failing heart
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Myocardial infarction
AT1-R
AT2-R
Experimental Model
Reference No.
1
1
mRNA/protein
SHR/2K-1C RHR/rat
87
1
1
mRNA/protein
Artery constriction/dog
113
1
1
mRNA/protein
Mechanical stetch/rat
81
1
3
mRNA/protein
Aortic banding/rat
89, 90
1
3
mRNA
Aortic banding/rat
112
1
3
mRNA
Aortic banding/rat
111
2
1
mRNA/protein
Hereditary myopathy/hamster
52
2
1
mRNA/protein
Human LV
95
2
1
Protein
Human atrium
101, 102
2
1
Protein
Human atrium/LV
99
2
1
Protein
Human atrium
102
2
3
Protein
Human LV
98
2
3
mRNA
Human LV
115
2
23
Protein
Human atrium/LV
97
1
1
mRNA/protein
Rat
88
3
3
Protein
Rat
151
Studies that simultaneously determined the expression level of AT1-R and AT2-R are provided. SHR indicates spontaneously
hypertensive rats; RHR, renovascular hypertensive rats, and LV, left ventricle.
aortic banding model,89,90 myocardial infarction,88 cardiomyopathy,52,114 and in mechanical stretch-induced hypertrophy of myocytes,81 whereas in failing human hearts the proportion of AT2-R to
AT 1 -R is relatively increased by AT 1 -R downregulation.95,97,98,101,103,115 The expression profiles of AT1-R and AT2-R
during cardiac remodeling are summarized in Table 2. In hereditary
myopathic hamsters, cardiac AT1-R increases in the hypertrophic
state but is downregulated in parallel with progressive heart failure,
whereas the expression of AT2-R increases during the heart failure
stage rather than during the hypertrophic state.52 In the aortic
banding model of rats, Lopez et al112 reported that the proportion of
AT2-R increases because of downregulation of AT1-R. Emulsion
autoradiography showed that AT1-R is present mainly in the myocardium of normal human hearts in situ and that its expression level
is downregulated during progressive heart failure.95 Recent human
studies showed that the expression of AT1-R is downregulated in
failing hearts95,97,98,101,103,115 and, conversely, that AT2-R is increased in the interstitial regions.99,102 The mechanism by which
AT2-R expression is increased in cardiac fibroblasts remains unknown. Ichiki et al24 and Kambayashi et al26 reported the upregulation of the AT2-R gene by IL-1b, insulin, and insulin-like growth
factors in R3T3 cells, and VSMCs. IL-1b is one of the important
cytokines mediating inflammation and may be involved in AT2-R
induction during the process of inflammation associated with cardiac
remodeling, as observed in experimental wound healing.116 Given
that most cells that abundantly express AT2-R in fetal mesenchymal
tissues are undifferentiated fibroblasts,117 similar cells may be
induced in the interstitial regions. Fetal mesenchymal fibroblasts,
which highly express AT2-R, express a substantial amount of
insulin-like growth factor-I and its receptor.118 Insulin and insulinlike growth factors might also be important for the abundant
expression of AT2-R in fibroblasts proliferating in fibrous regions.
Pathophysiological Role of AT2-R in
Remodeling of the Heart
The dominant expression of AT2-R in cardiac fibroblasts has
interesting pharmacological implications for the predicted actions
of AT1-R antagonists. Because circulating Ang II levels are
increased by administration of AT1-R antagonists11 and because
Ang II preferentially binds to cardiac AT2-R, AT2-R–mediated
actions are expected to be activated in failing hearts, especially in
cardiac fibroblasts. Using fibroblasts from myopathic hamster
hearts, Ohkubo et al52 determined that AT2-R has an inhibitory
effect on AT1-R–mediated synthesis of DNA and extracellular
collagenous protein, such as fibronectin and collagen type 1, and
that AT2-R stimulation inhibits the progression of interstitial
fibrosis in myopathic lesions. Several other studies also demonstrated an antigrowth role of AT2-R in the cardiovascular system,
shown by its inhibition of the proliferation of rat coronary
endothelial cells47 and transfected VSMCs, its modulation of
arterial hypertrophy, and fibrosis in Ang II–induced hypertensive
rats,119 and its prevention of Ang II–induced growth of cultured
neonatal rat myocytes.50 AT2-R–mediated apoptosis might be one
mechanism by which AT2-R induces an antigrowth effect.63,64
Indeed, apoptotic myocytes have been found to occur relatively
frequently in the border zone of infarcted human heart tissues,120
and researchers have speculated that AT2-R may affect changes in
myocardial structure by mediating apoptosis.121 Liu et al75 reported that the cardioprotective action of AT1-R antagonists is
mainly exerted by the selective stimulation of AT2-R, which is
mediated partly by the kinin/NO system. Ang II–induced cardiac
fibrosis is increased by chronic inhibition of NO synthase,122 and
generation of coronary kinin mediates NO release after Ang II
receptor stimulation.123 ATR2-R–mediated activation of the kinin/NO system also is involved in pressure natriuresis and
diuresis of the kidneys.78,79
The AT2-R in cardiac myocytes may have an additional action
distinct from the effect in cardiac fibroblasts. In mice developed for
cardiomyocyte-specific overexpression of AT2-R, with use of an
a-myosin heavy chain promoter, Ang II–induced positive chronotropic action is inhibited (Figure 3).54 In myocytes from neonatal rat
hearts expressing both AT1-R and AT2-R, Booz et al50 found that
AT2-R stimulation inhibits Ang II–induced myocyte hypertrophy by
decreasing the protein-to-DNA ratio and increasing protein degradation. Kijima et al81 reported that AT2-R in hypertrophic myocytes at
least partially exerts an inhibitory effect on AT1-R–mediated positive
chronotropic or hypertrophic actions by showing upregulation of
AT2-R in stretch-induced myocyte hypertrophy.
Cellular Localization and Function of AT2-R
in the Kidneys
Ang II has multiple effects on renal function, including modulation
of renal blood flow, glomerular filtration rate, tubular epithelial
transport, renin release, and cellular growth.124,125 Autoradiography
Matsubara
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Figure 3. Attenuated response of cardiac-specific overexpression mice of AT2-R to Ang II–induced pressor (upper panel) and
chronotropic (lower panel) actions. Mice were anesthetized with
pentobarbital, and blood pressure and heart rate were directly
measrued with catheters placed in the carotid artery. After 10
minutes of captopril administration (30 mg/kg body weight), Ang
II diluted in saline was infused directly into the catheter at different doses in a volume of 10 mL. To examine the effect of
PD123319, PD123319 (10 mg/kg) was infused into mice (n58)
pretreated with captrpril, and after 20 minutes, Ang II was
infused. The results are expressed as means6SE. *P,0.01,
†P,0.05 vs the levels in wild-type mice.
coupled with competitive binding studies has been used to characterize the distribution of Ang II receptor subtypes in renal tissue. By
use of these techniques, the distribution of AT1-R and AT2-R
subtypes within the kidney was shown to be species-dependent. For
example, in the rat and rabbit kidneys, Ang II receptors are
essentially of the AT1-R subtype,126 –130 whereas both AT1-R and
AT2-R are present within the kidney of the opossum and primates,
including humans.128 –133 The distribution of renal Ang II receptors
has been studied most extensively in the rat, where the AT1-R
binding sites are located predominantly in the glomeruli, the renal
tubules, and the renal vasculature.134,135 These observations in the rat
kidney were further confirmed at mRNA levels using polymerase
chain reaction and in situ hybridization136 –138; strong AT1-R mRNA
signals were detected in the glomerulus, proximal tubules, cortical
blood vessels, and collecting ducts. Weaker AT1-R mRNA signals
were present in the medullary thick ascending limb and medullary
collecting ducts. Within the rat glomerulus, AT1-R mRNA was
localized in mesangial areas, predominantly at the vascular pole and
on the terminal portion of the afferent arteriole. In contrast, using
mutant mice with a targeted replacement of the AT1-R loci by the
lacZ, Sugaya et al139 detected strong lacZ staining in both afferent
and efferent arterioles, which agreed with another finding involving
the use of polyclonal antisera for rat AT1-R.140
Analyses using Northern blot7 or in situ hybridization137 indicated
that AT2-R mRNA is not present in rat or mouse kidneys. However,
autoradiography revealed that in the rabbit, the fibrous sheath around
the kidney contains AT2-R binding sites141 and that in the rhesus
monkey, AT2-R binding sites are present on the juxtaglomerular
apparatus and vasculature in the renal cortex.128 With respect to
localization of Ang II receptor subtypes in the human kidney, all
studies have been performed on the protein level by autoradiography
using [125I]-Ang II as a ligand.130,132,133 Grone et al132 and Goldfarb
et al133 demonstrated AT1-R binding sites predominantly in the
glomeruli and tubulointerstitium, whereas AT2-R is the major subtype in large cortical blood vessels. In contrast, Sechi et al130
reported that AT1-R is present primarily in both glomeruli and
cortical blood vessels and that AT2-R protein is not expressed in the
December 14/28, 1998
1187
human kidney. Analysis of the human renal cortex using in situ
hybridization showed strong AT1-R mRNA signals localized in
interlobular arteries and tubulointerstitial fibrous regions and weaker
signals detected in glomeruli and proximal tubules.142 AT2-R mRNA
signals were highly localized in interlobular arteries,142 suggesting a
role of AT2-R in renal blood flow, which agrees with the diuretic
effect of AT2-R antagonists.143 The findings from a study of AT2-R
null mice indicate AT2-R involvement in the formation of the
embryonic ureter by the promotion of the mesenchymal cell apoptosis.144 Lo et al78 isolated tubular function from hemodynamic action
by maintaining a constant renal blood flow and found that the AT2-R
antagonist PD123319 markedly and rapidly increased diuresis and
natriuresis from the rat kidney. Inagami et al5 also described AT2-R
knockout mice as not having a diuretic response to PD123319.
Siragy et al74 reported that AT2-R stimulates renal production of
cGMP in response to Na depletion and that this effect is mediated by
NO production.77 Madrid et al79 also observed that the activation of
the NO/cGMP system by AT2-R impaired pressure diuresis. Arima et
al145 reported, with use of microperfused afferent arteriole, that
selective activation of AT2-R causes endothelium-dependent vasodilation via a cytochrome P-450 pathway, possibly by epoxyeicosatrienoic acids, which suggests that glomerular blood flow is partly
regulated by the AT2-R in an endothelium-dependent manner.
Pathophysiological Function of the AT2-R
Identified by Gene-Manipulated Animals
Ichiki et al9 and Hein et al10 used targeted deletion to eliminate the
gene encoding the AT2-R in mice. The resultant AT2-R null mice
exhibited elevated pressor sensitivity in response to intravenous
infusion of Ang II,9,10 and their basal blood pressure also increased.9
However, because AT2-R expression in the adult vasculature is very
low, the underlying mechanism remains unclear. Cardiac targeted
overexpression of AT2-R in mice was recently generated using an
a-myosin heavy chain promoter.54 No obvious morphological
changes were observed in the heart, electrocardiograms were normal,
and no arrhythmia or conduction block was seen. Infusion of Ang II
increased blood pressure and heart rate dose-dependently in wildtype mice, whereas in AT2-R transgenic mice, these hemodynamic
responses were inhibited markedly without affecting cardiac contractility (Figure 3). This effect was observed at a physiological Ang
II concentration range that did not stimulate catecholamine release,
suggesting that AT2-R decreases the sensitivity of pacemaker cells to
Ang II. Tsutsumi et al have used a VSMC-specific a-actin promoter
to generate transgenic mice that overexpress the AT2-R in the
vascular system (unpublished data, 1998). Although the basal blood
pressure of this transgenic mouse does not differ from that in
wild-type mice, the pressor effect by chronic Ang II infusion was
abolished, and Ang II–induced contraction of the abdominal artery
was significantly increased by an AT2-R inhibitor. The increased
sensitivity of AT2-R knockout mice to the pressor effect of Ang II
might be explained partly by lack of AT2-R–mediated negative
chronotropic action as well as by the reduction of vascular resistance.
Summary and Clinical Applications for
AT1-R Antagonists
In the near future, several AT1-R antagonists will be used for
treatment of cardiovascular and renal diseases. However, clinicians
should understand the differences in pharmacological effects between AT1-R antagonists and ACE inhibitors. Treatment with AT1-R
antagon causes an increase in plasma Ang II level, which selectively
stimulates AT2-R12 (Figure 4). As mentioned above, AT2-R stimulation inhibits cardiac fibroblast growth and extracellular matrix
formation and exerts a negative chronotropic effect, indicating that
AT2-R stimulation has a novel cardioprotective effect. Moreover, in
human hearts, the distribution ratio of the AT2-R is high, and its
expression is increased further during heart failure by downregulation of the AT1-R.95,97,98,103,115 The activation of the kinin/NO/cGMP
system mediated through the AT2-R is involved partially or dominantly in the cardiovascular and renal effects of the AT2-R, raising
the possibility that AT2-R stimulation has a similar effect to that
1188
Angiotensin II Type 2 Receptor
Figure 4. Comparison of potential pharmacological actions
expected by application of AT1-R antagonists and ACE
inhibitors.
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exerted by ACE inhibitors such as activation of the kinin/NO system.
In fact, Schieffer et al146 reported that ACE inhibitors and AT1-R
antagonists are equally effective in preventing ventricular remodeling after myocardial infarction. Very recently, an evaluation of
losartan in the elderly compared the effectiveness of the AT1-R
antagonist losartan and the ACE inhibitor captopril in elderly heart
failure patients, and the results showed that losartan was more
beneficial than captopril as evidenced by a lower rate of sudden
death and hospitalization.147 These beneficial effects might be partly
explained by the potential effect mediated by AT2-R. Because
blockade of the renin-angiotensin system is essential for the management of patients with heart failure or renal diseases148 –151 and
because AT1-R antagonists probably will be used widely for treatment of patients with cardiovascular and renal diseases in the near
future, this novel tissue-protective effect of AT2-R should be
confirmed by clinical studies.
Acknowledgment
This study was supported in part by research grants from the
Ministry of Education, Science and Culture, Japan, the Study Group
of Molecular Cardiology, and Japan Medical Association and Japan
Smoking Foundation.
References
1. Peach MJ. Renin-angiotensin system: biochemistry and mechanisms of
action. Physiol Rev. 1987;57:413– 435.
2. Paul M, Bachman J, Ganten D. The tissue renin-angiotensin system in
cardiovascular disease. Trends Cardiovasc Med. 1992;2:94 –99.
3. Inagami T, Kitami Y. Angiotensin II receptor: molecular cloning,
functions, and regulation. Hyper Res. 1994;17:87–97.
4. Timmermans PB, Wong PC, Chiu AT, Herblin WF, Benfield P, Carini
DJ, Lee RJ, Wexler RR, Saye JA, Smith RD. Angiotensin II receptors
and angiotensin II receptor antagonists. Pharmacol Rev. 1993;45:
205–251.
5. Inagami T, Eguchi S, Tsuzuki S, Ichiki T. Angiotensin II receptors AT1
and AT2: new mechanisms of signaling and antagonistic effects of AT1
and AT2. Jpn Circ. 1997;61:807– 813.
6. Unger T, Chung O, Csikos T, Culman J, Gallinat S, Gohlke P, Meffert
S, Stoll M, Stroth U, Shu YZ. Angiotensin receptors. J Hypertens.
1996;14(suppl 5):S95–S103.
7. Kambayashi Y, Bardhas S, Takahashi K, Tsuzuki S, Inui H, Hamakubo
T, Inaga T. Molecular cloning of a novel angiotensin II receptor isoform
involved in phosphotyrosine phosphatase inhibition. J Biol Chem. 1993;
268:24543–24546.
8. Mukoyama M, Nakajima M, Horiuchi M, Sasamura H, Pratt RE, Dzau
VJ. Expression cloning of type 2 angiotensin II receptor reveals a unique
class of seven-transmembrane receptors. J Biol Chem. 1993;268:
24539 –24542.
9. Ichiki T, Labosky PA, Shiota C, Okuyama S, Inagawa Y, Fogo A,
Niimura F, Ichikawa I, Hogan BLM, Inagami T. Effects on blood
pressure and exploratory behavior of mice lacking angiotensin II type-2
receptor. Nature. 1995;377:748 –750.
10. Hein L, Barsh GS, Pratt, RE, Dzau VJ, Koblik BK. Behavioral and
cardiovascular effects of disrupting the angiotensin II type-2 receptor
gene in mice. Nature. 1995;377:744 –747.
11. Christen Y, Waeber B, Nussberger J, Porchet M, Borland RM, Lee RJ,
Maggon K, Shum L, Timmermans PB, Brunner HR. Oral administration
of DuP 753, a specific angiotensin II receptor antagonist, to normal male
volunteers. Inhibition of pressor response to exogenous angiotensin I
and II. Circulation. 1991;83:1333–1342.
12. Bernstein KE, Alexander W. Counterpoint: molecular analysis of the
angiotensin II receptor. Endocr Rev. 1992;13:381–386.
13. Millan MA, Carvallo P, Izumi SI, Zemel S, Catt KJ, Aguilera G. Novel
sites of expression of functional angiotensin II receptors in the late
gestation fetus. Science. 1989;244:1340 –1342.
14. Grady EF, Sechi LA, Griffin CA, Schambolan M, Kalinucle JE.
Expression of AT2 receptors in the developing rat fetus. J Clin Invest.
1991;88:901–933.
15. Heerding JN, Yee DK, Jacobs SL, Fluharty SJ. Mutational analysis of
the angiotensin II type 2 receptor: contribution of conserved extracellular amino acids. Regul Pept. 1997;72:97–103.
16. Nakajima M, Mukoyama M, Pratt RE, Horiuchi M, Dzau VJ. Cloning of
cDNA and analyses of the gene for mouse angiotensin II type 2 receptor.
Biochem Biophys Res Commun. 1993;197:393–399.
17. Ichiki T, Herold CL, Kambayashi Y, Bardhan S, Inagami T. Cloning of
the cDNA and the genomic DNA of the mouse angiotensin II type 2
receptor. Biochim Biophys Acta. 1994;1189:247–250.
18. Tsuzuki S, Ichiki T, Nakakubo H, Kitami Y, Guo D-F, Shirai H, Inagami
T. Molecular cloning and expression of the gene encoding human
angiotensin II type 2 receptor. Biochem Biophys Res Commun. 1994;
200:1449 –1454.
19. Koike G, Horiuchi M, Yamada T, Szpirer C, Jacob HJ, Dzau VJ. Human
type 2 angiotensin II receptor gene: cloned, mapped to the X chromosome, and its mRNA is expressed in the human lung. Biochem
Biophys Res Commun. 1994;203:1842–1850.
20. Martin MM, Su B, Elton TS. Molecular cloning of the human angiotensin II type 2 receptor DNA. Biochem Biophys Res Commun. 1994;
205:645– 651.
21. Kizima K, Matsubara H, Murasawa S, Maruyama K, Ohkubo N, Mori
Y, Inada M. Regulation of angiotensin II type 2 receptor gene by the
protein kinase C– calcium pathway. Hypertension. 1996;27:529 –534.
22. Kizima K, Matsubara H, Murasawa S, Maruyama K, Mori Y, Inada M.
Gene transcription of angiotensin II type 2 receptor is repressed by
growth factors and glucocorticoids in PC12 cells. Biochem Biophys Res
Commun. 1995;216:359 –366.
23. Murasawa S, Matsubara H, Kijima K, Maruyama K, Ohkubo N, Mori Y,
lwasaka T, Inada M. Down-regulation by cAMP of angiotensin II type
2 receptor gene expression in PC12 cells. Hypertens Res. 1996;19:
271–279.
24. Ichiki T, Kambayashi Y, Inagami T. Multiple growth factors modulate
mRNA expression of angiotensin II type-2 receptor in R3T3 cells. Circ
Res. 1995;77:1070 –1076.
25. Dudley DT, Summerfelt RM. Characterization of angiotensin II (AT2)
binding sites in R3T3 cells. Regul Pept. 1933;44:199 –206.
26. Kambayashi Y, Bardhan S, Inagami T. Peptide growth factors markedly
decrease the ligand binding of angiotensin II type 2 receptor in rat
cultured vascular smooth muscle cells. Biochem Biophys Res Commun.
1993;194:478 – 482.
27. Ichiki T, Inagami T. Transcriptional regulation of the mouse angiotensin
II type 2 receptor gene. Hypertension. 1995;25:720 –725.
28. Ichiki T, Kambayashi Y, Inagami T. Differential inducibility of angiotensin II AT2 receptor between SHR and WKY vascular smooth muscle
cells. Kidney Int Suppl. 1996;55:S14 –S17.
29. Kambayashi Y, Ichild T, Inagami T. Insulin and insulin-like growth
factors induce expression of angiotensin type-2 receptor in vascular
smooth muscle cells. Eur J Biochem. 1996;239:558 –565.
30. Viswanathan M, Saavedra JM. Expression of angiotensin II AT2
receptors in the rat skin during experimental wound healing. Peptides.
1992;13:783–786.
31. Bondy CA, Werner H, Roberts CT, LeRoith D. Cellular pattern of
insulin-like growth factor-I and type I IGF receptor gene expression in
early organogenesis: comparison with IGF-II gene expression. Mol
Endocrinol. 1990;4:1386 –1398.
32. Murasawa S, Matsubara H, Urakami M, Inada M. Regulatory elements
that mediate expression of the gene for the angiotensin II type 1a
receptor for the rat. J Biol Chem. 1993;268:26996 –27003.
Matsubara
Downloaded from http://circres.ahajournals.org/ by guest on July 31, 2017
33. Murasawa S, Matsubara H, Mori Y, Kijima K, Maruyama K, Inada M.
Identification of a negative cis-regulatory element and trans-acting
protein that inhibit transcription of the angiotensin II type 1a receptor
gene. J Biol Chem. 1995;270:24282–24286.
34. Murasawa S, Matsubara H, Kanasaki M, Kijima K, Maruyama K,
Tsukaguchi H, Mori Y, Inada M. Characterization of glucocorticoid
response element of rat angiotensin II type 1 receptor gene. Biochem
Biophys Res Commun. 1995;209:832– 840.
35. Guo DF, Uno S, Ishihata A, Nakamura N, Inagami T. Identification of
a cis-acting glucocorticoid response element in the rat angiotensin II
type 1A promoter. Circ Res. 1995;77:249 –257.
36. Horiuchi M, Koike J, Yamada T, Mukoyama M, Nakajima M, Dzau VJ.
The growth-dependent expression of angiotensin II type 2 receptor is
regulated by transcription factors interferon regulatory factor-1 and -2.
J Biol Chem. 1995;270:20225–20230.
37. Horiuchi M, Yamada T, Hayashida W, Dzau VJ. Interferon regulatory
factor-1 up-regulates angiotensin II type 2 receptor and induces apoptosis. J Biol Chem. 1997;272:11952–11958.
38. Goto M, Mukoyama M, Suga S, Matsumoto T, Nakagawa M, Ishibashi
R, Kasahara M, Sugawara A, Tanaka I, Nakao K. Growth-dependent
induction of angiotensin II type 2 receptor in rat mesangial cells. Hypertension. 1997;30:358 –362.
39. Bottari SP, King IN, Reichlin S, Dahlstroem I, Lydon N, de Gasparo M.
The angiotensin AT2 receptor stimulates protein tyrosine phosphatase
activity and mediates inhibition of particulate guanylate cyclase.
Biochem Biophys Res Commun. 1992;183:206 –211.
40. Nahmias C, Cazaubon SM, Briend-Sutren MM, Lazard D, Villageois P,
Strosberg AD. Angiotensin II AT2 receptors are functionally coupled to
protein tyrosine dephosphorylation in NIE-115 neuroblastoma cells.
Biochem J. 1995;306:87–92.
41. Meffert S, Stoll M, Steckelings UM, Bottari SP, Unger T. The angiotensin II type 2 receptor inhibits proliferaton and promotes differentiation in PC12W cells. Mol Cell Endocrinol. 1996;122:59 – 67.
42. Ozawa Y, Suzuki Y, Murakami K, Miyazaki H. The angiotensin II type
2 receptor primarily inhibits cell growth via pertussis toxin-sensitive G
proteins. Biochem Biophys Res Commun. 1996;228:328 –333.
43. Tsuzuki S, Eguchi S, Inagami T. Inhibition of cell proliferation and
activatoin of protein tyrosine phosphatase mediated by angiotensin II
type 2 (AT2) receptor in R3T3 cells. Biochem Biophys Res Commun.
1996;228:825– 830.
44. Tsuzuki S, Matoba T, Eguchi S, Inagami T. Angiotensin II type 2
receptor inhibits cell proliferation and activates tyrosine phosphatase.
Hypertension. 1996;28:916 –918.
45. Geisterifer AA, Peach MJ, Owens GK. Angiotensin II induces hypertrophy, not hyperplasia, of cultured rat aortic smooth muscle cells. Circ
Res. 1988;62:749 –756.
46. Sadoshima J, Izumo S. The heterotrimeric Gq protein-coupled angiotensin II receptor activates p21ras via the tyrosine kinase-Shc-Grb2-Sos
pathway in cardiac myocytes. EMBO J. 1996;15:775–787.
47. Stoll M, Steckelings UM, Paul M, Bottari SP, Metzger R, Unger T. The
angiotensin AT2-receptor mediates inhibition of cell proliferation in
coronary endothelial cells. J Clin Invest. 1995;95:651– 657.
48. Nakajima M, Hutchinson HG, Fuginaga M, Hayashida W, Zhang L,
Horiuchi M, Pratt RE, Dzau VJ. The angiotensin II type 2 (AT2)
antagonizes the growth effects of the AT1 receptor: gain-of-function
study using gene transfer. Proc Natl Acad Sci U S A. 1995;82:
10663–10667.
49 Janiak P, Pillon A, Prost JF, Vilaine JP. Role of angiotensin subtype 2
receptor in neointima formation after vascular injury. Hypertension.
1992;20:737–745.
50. Booz GW, Baker KM. Role of type 1 and type 2 angiotensin receptors
in angiotensin II-induced cardiomyocyte hypertrophy. Hypertension.
1996;28:635– 640.
51. van Kesteren CA, van Heugten HA, Lamers JM, Saxena PR,
Schalekamp MA, Danser AH. Angiotensin II-mediated growth and
antigrowth effects in cultured rat cardiac myocytes and fibroblasts. J
Mol Cell Cardiol. 1997;29:2147–2157.
52. Ohkubo N, Matsubara H, Nozawa Y, Mori Y, Murasawa S, Kijima K,
Maruyama K, Masaki H, Iwasaka T, Inada M. Angiotensin type 2
receptors are re-expressed by cardiac fibroblasts from failing myopathic
hamster hearts and inhibit cell growth and fibrillar collagen metabolism.
Circulation. 1997;96:3954 –3962.
53. Mazzocchi G, Malendowicz LK, Gottardo G, Rebuffat P, Nussdorfer
GG. Angiotensin II stimulates DNA synthesis in rat adrenal zona glo-
54.
55.
56.
57.
58.
59.
60.
61.
62.
63.
64.
65.
66.
67.
68.
69.
70.
71.
72.
73.
74.
75.
December 14/28, 1998
1189
merulosa cells: receptor subtypes involved and possible signal transduction mechanism. Endocr Res. 1997;23:191–203.
Masaki H, Kurihara I, Yamaki A, Inomata N, Nozawa Y, Mori Y,
Murasawa S, Kizima K, Maruyama K, Horiuchi M, Dzau VVJ,
Takahashi H, iwasaka T, Inada M, Matsubara H. Cardiac-specific overexpression of angiotensin II, AT2 receptor causes attenuated response to
AT1 receptor-mediated pressor and chronotropic effects. J Clin Invest.
1998;101:527–535.
Maric C, Aldred GP, Harris PJ, Alcorn D. Angiotensin II inhibits growth
of cultured embroyonic renomedullary interstitial cells through the AT2
receptor. Kidney Int. 1998;53:92–99.
Horiuchi M, Hayashida W, Kambe T, Yamada T, Dzau VJ. Angiotensin
type 2 receptor dephosphorylates Bcl-2 by activating mitogen-activated
protein kinase phosphatase-1 and induces apoptosis. J Biol Chem. 1997;
272:19022–19026.
Bedecs K, Elbaz N, Sutren M, Masson M, Susini C, Strosberg AD,
Nahmias C. Angiotensin II type 2 receptors mediate inhibition of
mitogen-activated protein kinase cascade and functional activation of
SHP-1 tyrosine phosphatase. Biochem J. 1997;325:449 – 454.
Kang J, Sumners C, Posner P. Angiotensin II type 2 receptor-modulated
changes in potassium currents in cultured neurons. Am J Physiol. 1993;
265:C607–C616.
Kang J, Posner P, Sumners C. Angiotensin II type 2 receptor stimulation
of neuronal K1 currents involves an inhibitory GTP binding protein.
Am J Physiol. 1994;267:C1389 –C1397.
Zhu M, Gelband CH, Moore JM, Posner P, Sumners C. Angiotensin II
type 2 receptor stimulation of neuronal delayed-rectifier potassium
current involves phospholipase A2 and arachidonic acid. J Neurosci.
1998;18:679 – 686.
Buisson B, Laflamme L, Bottari SP, de Gasparo M, Gallo-Payet N,
Payet MD. A G protein is involved in the angiotensin AT2 receptor
inhibition of the T-type calcium current in nondifferentiated NG108 –15
cells. J Biol Chem. 1995;270:1670 –1674.
Steckelings UM, Bottari SP, Unger T. Angiotensin receptor subtypes in
the brain. Trends Pharmacol Sci. 1992;13:365–368.
Bottari SP, King IN, Bogdal Y, Reichlin S, Dahlstroem I, Lydon N, de
Gasparo M. The angiotensin II AT2 receptor stimulates phosphotyrosine
phosphatase activity and mediates inhibition of particulate guanylate
cyclase. Biochem Biophys Res Commun. 1992;183:206 –211.
Brechler V, Reichlin S, de Gasparo M, Bottari SP. Angiotensin II
stimulates protein tyrosine phosphatase activity through a G-protein
independent mechanism. Receptors Channels. 1994;2:89 –98.
Tanaka M, Ohnishi J, Ozawa Y, Sugimoto M, Usuki S, Naruse M.
Characterization of angiotensin II receptor type 2 during differentiation
and apoptosis of rat ovarian cultured granules cells. Biochem Biophys
Res Commun. 1995;207:593–598.
Yamada T, Horiuchi M, Dzau VJ. Angiotensin II type 2 receptor
mediates programmed cell death. Proc Natl Acad Sci U S A. 1996;93:
156 –160.
Hayashida W, Horiuchi M, Dzau VJ. Intracellular third loop domain of
angiotensin II type-2 receptor: role in mediating signal transduction and
cellular function. J Biol Chem. 1996;271:21985–21992.
Zhang J, Pratt RE. The AT2 receptor selectively associates with Gia2 and
Gia3 in the rat fetus. J Biol Chem. 1996;271:15026 –15033.
Cigola E, Kajstura J, Li B, Meggs LG, Anversa P. Angiotensin II
activates programmed myocyte cell death in vitro. Exp Cell Res. 1997;
231:363–371.
Wiemer G, Scholkens BA, Busse R, Wagner A, Heitsch H, Linz W. The
functional role of angiotensin II-subtype 2-receptors in endothelial cells
and isolated ischemic rat hearts. Pharmacol Lett. 1993;3:24 –27.
Boulanger CM, Caputo L, Levy BI. Endothelial AT1-mediated release of
nitric oxide decreases angiotensin II contractions in rat carotid artery.
Hypertension. 1995;26:752–757.
Seyedi N, Xu XB, Najiletti A, Hintze TH. Coronary kinin generation
mediates nitric oxide release after angiotensin receptor stimulation.
Hypertension. 1995;26:164 –170.
Munzenmaier DH, Greene AS. Stimulation of soluble guanylate cyclase
activity by angiotensin II is mediated by a non-AT1 receptor mechanism
in rat aorta. FASEB J. 1994;8:A367. Abstract.
Siragy HM, Carey RM. The subtype-2 (AT2) angiotensin receptor regulates renal cyclic guanosine 31 receptor-mediated prostaglandin E2
production in conscious rats. J Clin Invest. 1996;97:1978 –1982.
Liu YH, Yang XP, Sharov VG, Nass O, Sabbah HN, Peterson E,
Carretero OA. Effects of angiotensin-converting enzyme inhibitors and
angiotensin II type 1 receptor antagonists in rat with heart failure. Role
1190
76.
77.
78.
79.
80.
81.
82.
Downloaded from http://circres.ahajournals.org/ by guest on July 31, 2017
83.
84.
85.
86.
87.
88.
89.
90.
91.
92.
93.
94.
95.
96.
97.
Angiotensin II Type 2 Receptor
of kinins and angiotensin II type 2 receptors. J Clin Invest. 1997;99:
1926 –1935.
Gohlke P, Pees C, Unger T. AT2 receptor stimulation increases aortic
cyclic GMP in SHRSP by a kinin-dependent mechanism. Hypertension.
1998;31:349 –355.
Siragy HM, Carey RM. The subtype 2 (AT2) angiotensin receptor
mediates renal production of nitric oxide in conscious rats. J Clin Invest.
1997;100:264 –269.
Lo M, Liu KL, Lantelme P, Sassard J. Subtype 2 of angiotensin II
receptors controls pressure-natriuresis in rats. J Clin Invest. 1995;95:
1394 –1397.
Madrid MI, Garcia-Salom M, Tornel J, de Gasparo M, Fenoy FJ. Effect
of interactions between nitric oxide and angiotensin II on pressure
diuresis and natriuresis. Am J Physiol. 1997;273:R1676 –R1682.
Matsubara H, Kanasaki M, Murasawa S, Tsukaguchi Y, Nio Y, Inada M.
Differential gene expression and regulation of angiotensin II receptor
subtypes in rat cardiac fibroblasts and cardiomyocytes in culture. J Clin
Invest. 1994;93:1592–1601.
Kijima K, Matsubara H, Komuro I, Yazaki Y, Inada M. Mechanical
stretch induces enhanced expression of angiotensin II receptors in
neontatal rat cardiac myocytes. Circ Res. 1996;79:887– 897.
Schorb W, Booz GW, Dostal DE, Conrad KM, Chang KC, Baker KM.
Angiotensin II is mitogenic in neonatal rat cardiac fibroblasts. Circ Res.
1993;72:1245–1254.
Crabos M, Roth M, Hahn AWA, Erne P. Characterization of angiotensin
II receptors in cultured adult rat cardiac fibroblasts. J Clin Invest.
1994;93:2372–2378.
Villarreal FJ, Kim NN, Ungab GD, Printz MP, Dillmann W. Identification of functional angiotensin II receptors on rat cardiac fibroblasts.
Circulation. 1993;88:2849 –2861.
Meggs LG, Coupet J, Huang H, Cheng W, Li P, Capasso JM, Homcy CJ,
Anversa P. Regulation of angiotensin II receptors on ventricular
myocytes after myocardial infarction in rats. Circ Res. 1993;72:
1149 –1162.
Reiss K, Capasso JM, Huang H, Meggs LG, Li P, Anversa A. Ang II
receptors c-myc, and c-jun in myocytes after myocardial infarction and
ventricular failure. Am J Physiol. 1993;264:H760 –H769.
Suzuki J, Matsubara H, Urakami M, Inada M. Rat angiotensin II (type
1A) receptor mRNA regulation and subtype expression in myocardial
growth and hypertrophy. Circ Res. 1993;73:439 – 447.
Nio Y, Matsubara H, Murasawa S, Kanasaki M, Inada M. Regulation of
gene transcription of angiotensin II receptor subtypes in myocardial
infarction. J Clin Invest. 1995;95:46 –54.
Harada K, Komuro I, Shiojima I, Hayashi D, Kudoh S, Mizuno T,
Kijima K, Matsubara H, Sugaya T, Murakami K, Yazaki Y. Pressure
overload induces cardiac hypertrophy in angiotensin II type 1A
knockout mice. Circulation. 1998;97:1952–1959.
Harada K, Komuro I, Shiojima I, Hayashi D, Kudoh S, Mizuno T,
Kijima K, Matsubara H, Sugaya T, Murakami K, Yazaki Y. Acute
pressure overload could induce hypertrophic responses in the heart of
angiotensin II type 1a knockout mice. Circ Res. 1998;82:779 –785.
Sechi LA, Griffin CA, Grady EF, Kalinyak JE, Schambelan M. Characterization of angiotensin II receptor subtypes in rat heart. Circ Res.
1990;71:1482–1489.
Schanmugam S, Corvol P, Gasc JM. Angiotensin II type 2 receptor
mRNA expression in the developing cardiopulmonary system of the rat.
Hypertension. 1996;28:91–97.
Feolde E, Vigne P, Frelin C. Angiotensin-II receptor subtypes and
biological responses in rat heart. J Mol Cell Cardiol. 1994;25:
1359 –1367.
Johnson MC, Aguilera G. Angiotensin II receptor subtypes and coupling
to signaling systems in cultured fetal fibroblasts. Endocrinology. 1991;
129:1266 –1274.
Tsutsumi Y, Matsubara H, Ohkubo N, Mori Y, Nozawa Y, Murasawa S,
Kijima K, Maruyama K, Masaki H, Moriguchi Y, Shibasaki Y,
Kamihata H, Inada M, Iwasaka T. Angiotensin II type 2 receptor is
upregulated in human heart with interstitial fibrosis, and cardiac fibroblasts are the major celltype for its expression. Circ Res. 1998;83:
1035–1046.
Urata H, Healy B, Stewart RW, Bumpus FM, Husain A. Angiotensin II
receptors in normal and failing human hearts. J Clin Endocrinol Metab.
1989;69:54 – 66.
Regitz-Zagrosek V, Friedel N, Heymann A, Bauer P, Neuss M, Rolfs A,
Steffen C, Hildebrandt A, Hetzer R, Fleck E. Regulation, chamber
98.
99.
100.
101.
102.
103.
104.
105.
106.
107.
108.
109.
110.
111.
112.
113.
114.
115.
116.
117.
118.
localization, and subtype distribution of angiotensin II receptors in
human hearts. Circulation. 1995;91:1461–1471.
Asano K, Dutcher DL, Port JD, Minobe WA, Tremmel KD, Roden RL,
Bohlmeyer TJ, Bush EW, Jenkin MJ, Abraham WT, Raynolds MV,
Zisman LS, Perryman MB, Bristow MR. Selective downregulation of
the angiotensin II AT1-receptor subtype in failing human ventricular
myocardium. Circulation. 1997;95:1193–1200.
Wharton J, Morgan K, Rutherford RAD, Catravas JD, Chester A,
Whitehead BF, Leval MR, Yacoub MH, Polak JM. Differential distribution of angiotensin AT2 receptor in the normal and failing human
heart. J Pharmacol Exp Ther. 1994;270:566 –571.
Nozawa Y, Haruno A, Oda N, Yamada S, Inabe K, Kimura R, Suzuki H.
Angiotensin II receptor subtypes in bovine and human ventricular myocardium. J Pharmacol Exp Ther. 1994;270:566 –571.
Rogg H, de Gasparo M, Graedel E, Stulz P, Burkart F, Eberhard M, Erne
P. Angiotensin II-receptor subtypes in human atria and evidence for
alterations in patients with cardiac dysfunction. Eur Heart J. 1996;17:
1112–1120.
Brink M, Erne P, de Gasparo M, Rogg H, Schmid A, Stulz P, Bullock
G. Localization of the angiotensin II receptor subtypes in the human
atrium. J Mol Cell Cardiol. 1996;28:1789 –1799.
de Gasparo M, Rogg H, Brink M, Wang L, Whitebread S, Bullock G,
Erine P. Angiotensin II receptor subtypes and cardiac function. Eur
Heart J. 1994;15:98 –103.
Brilla CG, Zhou G, Rupp H, Maisch B, Weber KT. Role of angiotensin
II and prostaglandin E2 in regulating cardiac fibroblast collagen
turnover. Am J Cardiol. 1995;76:8D–13D.
Neuss M, Regitz-Zagrosek V, Hildebrandt A, Fleck E. Human cardiac
fibroblasts express an angiotensin receptor with unusual binding characteristics which is coupled to cellular proliferation. Biochem Biophys
Res Commun. 1994;204:1334 –1339.
Neuss M, Regitz-Zagrosek V, Hildebrandt A, Fleck E. Isolation and
characterization of human cardiac fibroblasts form expanded adult
hearts. Cell Tissue Res. 1996;286:145–153.
Wan L, Eberhard M, Erne P. Stimulation of DNA and RNA synthesis in
cultured rabbit cardiac fibroblasts by angiotensin IV. Clin Sci (Colch).
1995;88:557–562.
Hanesworth JM, Sardinia MF, Krebs LLT, Hall KH, Harding JW.
Elucidation of a specific binding site for angiotensin II (3– 8) angiotensin IV in mammalian heart membranes. J Pharmacol Exp Ther. 1993;
266:1036 –1042.
Konishi H, Kuroda S, Inada Y, Fujisawa Y. Novel subtype of human
angiotensin II type 1 receptor: cDNA cloning and expression. Biochem
Biophys Res Commun. 1994;199:467– 474.
Siemens IR, Reagan LP, Yee DK, Fluharty SJ. Biochemical characterization of two distinct angiotensin AT2 receptor populations in murine
neuroblastoma NIE-115 cells. J Neurochem. 1994;62:2106 –2115.
Fujii N, Tanaka M, Ohnishi J, Yukawa K, Takimoto E, Shimada S,
Naruse M, Sugiyama F, Yamagi K, Murakami K, Miyazaki H. Alterations of angiotensin II receptor contents in hypertrophied hearts.
Biochem Biophys Res Commun. 1995;212:326 –333.
Lopez JJ, Lorell BH, Ingelfinger JR, Weinberg EO, Schunkert H,
Diamant D, Tang SS. Distribution and function of cardiac angiotensin
AT1- and AT2-receptor subtypes in hypertrophied rat hearts. Am J
Physiol. 1994;267:H844 –H852.
Lee Y-A, Liang C-S, Lee M-A, Lindpainter K. Local stress, not systemic
factors, regulate gene expression of the cardiac renin-angiotensin system
in vivo: a comprehensive study of all its components in the dog. Proc
Natl Acad Sci U S A. 1996;93:11035–11040.
Lambet C, Massillon Y, Meloche S. Upregulation of cardiac angiotensin
II AT1 receptors in congenital cardiomyopathic hamsters. Circ Res.
1995;77:1001–1007.
Haywood GA, Gullestad L, Katsuya T, Hutchinson HG, Pratt RE,
Horiuchi M, Fowler MB. AT1 and AT2 angiotensin receptor gene
expression in human heart failure. Circulation. 1997;95:1201–1206.
Viswanathan M, Saavedra JM. Expression of angiotensin 11 AT2
receptors in the rat skin during experimental wound healing. Peptides.
1992;13:783–786.
Grady EF, Sechi LA, Griffin CA, Schambolan M, Kalinucle JE.
Expression of AT2 receptors in the developing rat fetus. J Clin Invest.
1991;88:901–933.
Bondy CA, Werner H, Roberts CT, LeRoith D. Cellular pattern of
insulin-like growth factor (IGF-I) and type I IGF receptor gene
expression in early organogenesis: comparison with IGF-II gene
expression. Mol Endocrinol. 1990;4:1386 –1398.
Matsubara
Downloaded from http://circres.ahajournals.org/ by guest on July 31, 2017
119. Levy BI, Benessiano J, Henrion D, Caputa L, Heymes C, Duriez M,
Poitevlin P, Samuel L. Chronic blockade of AT2 subtype receptors
prevents the effect of angiotensin II on rat vascular structure. J Clin
Invest. 1996;98:418 – 425.
120. Saraste A, Pulkki K, Kallajold M, Hemriksen K, Paarvinen M, VoipioPulkki LK. Apoptosis in human acute myocardial infarction. Circulation. 1997;95:320 –323.
121. Dzau VJ, Horiuchi M. Differential expression of angiotensin receptor
subtypes in the myocardium: a hypothesis. Eur Heart J. 1996;17:
978 –980.
122. Hou J, Kato H, Cohen RA, Chobanian AV, Brecher P. Angiotensin
II-induced cardiac fibrosis in the rat is increased by chronic inhibition of
nitric oxide synthase. J Clin Invest. 1995;96:2469 –2477.
123. Seyedi N, Xu X, Nasjletti A, Hintze TH. Coronary kinin generation
mediates nitric oxide release after angiotensin receptor stimulation.
Hypertension. 1995;26:164 –170.
124. de Gasparo R, Levens NR. Pharmacology of angiotensin II receptors in
the kidney. Kidney Int. 1994;46:1486 –1491.
125. Douglas JG, Hopfer U. Novel aspect of angiotensin receptors and signal
transduction in the kidney. Annu Rev Physiol. 1995;56:649 – 669.
126. Edwards RM, Stack EJ, Weidley EF, Aiyar N, Keehan RM, Hill DT,
Weinstock J. Characterization of renal angiotensin II receptors using
subtype selective antagonists. J Pharmacol Exp Ther. 1992;260:
933–938.
127. Gauquelin G, Garcia R. Characterization of glomerular angiotensin II
receptor subtypes. Receptor. 1992;2:207–212.
128. Gibson RE, Thorpe HH, Cartwright ME, Frank JD, Schorn TW, Bunting
PB, Siegl PK. Angiotensin II receptor subtypes in renal cortex of rats
and rhesus monkeys. Am J Physiol. 1991;261:F512–F518.
129. Chang RS, Lotti VJ. Angiotensin II receptor subtypes in rat, rabbit and
monkey tissues: relative distribution and species dependency. Life Sci.
1991;49:1485–1490.
130. Sechi LA, Grady EF, Griffin CA, Kalinyak JE, Schambelan M. Distribution of angiotensin II receptor subtypes in rat and human kidney. Am J
Physiol. 1992;262:F236 –F240.
131. Jourdain M, Amiel C, Friedlander G. Modulation of Na-H exchange
activity by angiotensin II in opossum kidney cells. Am J Physiol.
1992;263:C1141–C1146.
132. Grone HJ, Simon M, Fuchs E. Autoradiographic characterization of
angiotensin receptor subtypes in fetal and human kidney. Am J Physiol.
1992;262:F326 –F331.
133. Goldfarb DA, Diz DI, Tubbs RR, Ferrario CM, Novick AC. Angiotensin
II receptor subtypes in the human renal cortex and renal cell carcinoma.
J Urol. 1994;151:208 –213.
134. De Leon H, Garcia R. Angiotensin II receptor subtypes in rat renal
preglomerular vessels. Receptor. 1992;2:253–260.
135. Chansel D, Vandenneersch S, Pham P, Ardaollou R. Characterization of
[H3]losartan receptors in isolated rat glomeruli. Eur J Pharmacol. 1993;
247:193–198.
136. Terada Y, Tomita K, Nonoguchi H, Marumo F. PCR localization of
angiotensin II receptor and angiotensinogen messenger RNAs in rat
kidney. Kidney Int. 1993;43:1251–1259.
137. Kakinuma Y, Fogo A, Inagami T, Ichikawa I. Intrarenal localization of
angiotensin II type 1 receptor messenger RNA in the rat. Kidney Int.
1993;43:1229 –1235.
December 14/28, 1998
1191
138. Meister B, Lippoldt A, Bunnemann B, Inagami T, Ganten D, Fuxe K.
Cellular expression of angiotensin type-1 receptor messenger RNA in
the kidney. Kidney Int. 1993;44:331–336.
139. Sugaya T, Nishimatsu S, Tanimoto K, Takimoto E, Yamagishi T,
Imamura K, Goto S, Imaizumi K, Hisada Y, Otsuka A, Fukamizu A,
Murakami K. Angiotensin II type 1a receptor-deficient mice with hypotension and hyperreninemia. J Biol Chem. 1995;270:18719 –18722.
140. Paxton WG, Runge M, Horaist C, Cohen C, Alexander RW, Bernstein
KE. Immunohistochemical localization of rat angiotensin II AT1
receptor. Am J Physiol. 1993;264:F989 –F995.
141. Herblin WF, Diamond SM, Timmermans PB. Localization of angiotensin II receptor subtypes in the rabbit adrenal and kidney. Peptides.
1991;12:581–584.
142. Matsubara H, Sugaya T, Murasawa S, Nozawa Y, Mori Y, Masaki H,
Maruyama K, Tsutumi Y, Shibasaki Y, Moriguchi Y, Tahaka Y,
Iwasaka T, Inada M. Tissue-specific expression of human angiotensin II
AT1 and AT2 receptors and cellular localization of subtype mRNSa in
adult human renal cortex using in situ hybridzation. Nephron. 1998;80:
25–34.
143. Keiser JA, Bjork FA, Hodges JC, Tayor DQ Jr. Renal hemodynamic and
excretory response to PD123319 and losartan, nonpeptide AT1 and AT2
subtype-specific angiotensin II ligands. J Pharmacol Exp Ther. 1992;
263:1154 –1160.
144. Miyazaki Y, Nishimura H, Harris RC, McKanna JM, Inagami T,
Ichikawa I. Angiotensin regulates embryonic development of the ureter
via type 1 (AT1) and type 2 (AT2) receptors. J Am Soc Neprhol.
1997;8:405A. Abstract.
145. Arima S, Endo Y, Yaoita H, Omata K, Ogawa S, Tsunoda K, Abe M,
Takeuchi K, Abe K, Ito S. Possible role of P-450 metabolite of arachidonic acid in vasodilator mechanism of angiotensin II type 2 receptor in
the isolated microperfused rabbit afferent arteriole. J Clin Invest. 1997;
100:2816 –2823.
146. Schieffer B, Wirger A, Meybrunn M, Seitz S, Holtz J, Riede UN,
Drexler H. Comparative effects of chronic angiotensin-converting
enzyme inhibition and angiotensin II type 1 receptor blockade on cardiac
remodeling after myocardial infarction in the rat. Circulation. 1994;89:
2273–2282.
147. Pitt B, Segal R, Martinez FA, Meurers G, Cowley AJ, Thomas I,
Deedwania P, Ney DE, Snavely DB, Chang PI. Randomised trial of
losartan versus captoril in patients over 65 with heart failure (evaluation of losartan in the elderly study, ELITE). Lancet. 1997;349:
747–752.
148. The CONSENSUS trial study group. Effects of enalapril on mortality in
severe congestive heart failure. N Engl J Med. 1987;315:1429 –1435.
149. The SOLVD investigators. Effect of enalapril on survival in patients
with reduced left ventricular ejection fractions and congestive heart
failure. N Engl J Med. 1991;325:293–302.
150. Maschio G, Alberti D, Janin G, Locatelli F, Mann JFE, Motolese M,
Ponticelli C, Ritz E, Zucchelli P. Effect of the angiotensin- convertingenzyme inhibitor benazepril on the progression of chronic renal insufficiency. N Engl J Med. 1996;334:939 –945.
151. Wolf K, Bruna RD, Bruckschlegel G, Schunkert H, Riegger GAJ, Kurtz
A. Angiotensin II receptor gene expression in hypertrophied left ventricles of rat hearts. J Hypertens. 1996;14:349 –354.
Pathophysiological Role of Angiotensin II Type 2 Receptor in Cardiovascular and Renal
Diseases
Hiroaki Matsubara
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Circ Res. 1998;83:1182-1191
doi: 10.1161/01.RES.83.12.1182
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