© 1998 American Heart Association, Inc.
Review |
Pathophysiological Role of Angiotensin II Type 2 Receptor in Cardiovascular and Renal Diseases
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 matsubah{at}takii.kmu.ac.jp
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Abstract |
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 Top Abstract IntroductionStructural Features of...Regulation of AT2-R...AT2-R–Mediated...Expression and Cellular...Regulation of Cardiac...Pathophysiological Role of...Cellular Localization and...Pathophysiological Function of...Summary and Clinical...References |
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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.
Key Words: angiotensin II receptor • angiotensin II type 2 receptor • angiotensin II AT2 receptor • angiotensin II type 1 receptor • angiotensin II AT1 receptor
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Introduction |
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TopAbstractIntroductionStructural Features of...Regulation of AT2-R...AT2-R–Mediated...Expression and Cellular...Regulation of Cardiac...Pathophysiological Role of...Cellular Localization and...Pathophysiological Function of...Summary and Clinical...References |
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The 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 signal-transduction
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 4 5 6 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.
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Structural Features of AT2-R |
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TopAbstractIntroductionStructural Features of...Regulation of AT2-R...AT2-R–Mediated...Expression and Cellular...Regulation of Cardiac...Pathophysiological Role of...Cellular Localization and...Pathophysiological Function of...Summary and Clinical...References |
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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 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 4 5 6 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, 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 19 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
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Regulation of AT2-R Gene Transcription and Expression |
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TopAbstractIntroductionStructural Features of...Regulation of AT2-R...AT2-R–Mediated...Expression and Cellular...Regulation of Cardiac...Pathophysiological Role of...Cellular Localization and...Pathophysiological Function of...Summary and Clinical...References |
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The gene expression of AT2-R is regulated by multiple factors (Table 1
). Increase in
intracellular CA2+ levels by Ca2+ 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 Ca2+ 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 the
upregulation of the AT2-R gene by interleukin (IL)-1ß,
insulin, and insulin-like growth factors in R3T3 cells and VSMCs.
IL-1ß 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 33 34 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 |
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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 serum-stimulated 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 signal-regulated 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
factor-induced ERK activity in NIE-115 cells is associated with
vanadate-sensitive 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
K+ currents60 and inhibits T-type
Ca2+ 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
Gi
2 and Gi3 proteins. In contrast, Cigola
et al69 reported that the stimulation of AT1-R
but not AT2-R induces apoptosis by
Ca2+-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
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Expression and Cellular Localization of AT2-R in the Heart |
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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 82 83 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 85 86
other researchers have obtained positive results.24 87 88 89 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 97 98 99 100 ; 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 30±2.7% and 8.2±1.4%, 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 97 98 99 100 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.
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Regulation of Cardiac AT2-R Expression During Cardiac Remodeling |
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TopAbstractIntroductionStructural Features of...Regulation of AT2-R...AT2-R–Mediated...Expression and Cellular...Regulation of Cardiac...Pathophysiological Role of...Cellular Localization and...Pathophysiological Function of...Summary and Clinical...References |
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Both AT1-R and AT2-R are upregulated to different extents in pathological conditions, such as cardiac hypertrophy,87 111 112 113 an 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 AT1-R is relatively increased by AT1-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-1ß, insulin, and
insulin-like growth factors in R3T3 cells, and VSMCs. IL-1ß 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 insulin-like growth factors might
also be important for the abundant expression of AT2-R in
fibroblasts proliferating in fibrous regions.
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Pathophysiological Role of AT2-R in Remodeling of the Heart |
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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 -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.
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P<0.05 vs the levels in wild-type mice. |
Cellular Localization and Function of AT2-R in the Kidneys |
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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 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,126 127 128 129 130 whereas both AT1-R and AT2-R are present within the kidney of the opossum and primates, including humans.128 129 130 131 132 133 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 137 138 ; 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 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.
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Pathophysiological Function of the AT2-R Identified by Gene-Manipulated Animals |
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TopAbstractIntroductionStructural Features of...Regulation of AT2-R...AT2-R–Mediated...Expression and Cellular...Regulation of Cardiac...Pathophysiological Role of...Cellular Localization and...Pathophysiological Function of...Summary and Clinical...References |
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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
-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 wild-type
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
-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 |
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TopAbstractIntroductionStructural Features of...Regulation of AT2-R...AT2-R–Mediated...Expression and Cellular...Regulation of Cardiac...Pathophysiological Role of...Cellular Localization and...Pathophysiological Function of...Summary and Clinical...References |
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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 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 149 150 151 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.
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Acknowledgments |
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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.
Received May 14, 1998; accepted September 23, 1998.
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References |
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TopAbstractIntroductionStructural Features of...Regulation of AT2-R...AT2-R–Mediated...Expression and Cellular...Regulation of Cardiac...Pathophysiological Role of...Cellular Localization and...Pathophysiological Function of...Summary and Clinical...References |
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C. M. Bove, Z. Yang, W. D. Gilson, F. H. Epstein, B. A. French, S. S. Berr, S. P. Bishop, H. Matsubara, R. M. Carey, and C. M. Kramer Nitric Oxide Mediates Benefits of Angiotensin II Type 2 Receptor Overexpression During Post-Infarct Remodeling Hypertension, March 1, 2004; 43(3): 680 - 685. [Abstract] [Full Text] [PDF]
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 H. Suzuki, T. Yamamoto, N. Ikegaya, and A. Hishida Dietary salt intake modulates progression of antithymocyte serum nephritis through alteration of glomerular angiotensin II receptor expression Am J Physiol Renal Physiol, February 1, 2004; 286(2): F267 - F277. [Abstract] [Full Text] [PDF]
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B. I. Levy Can Angiotensin II Type 2 Receptors Have Deleterious Effects in Cardiovascular Disease?: Implications for Therapeutic Blockade of the Renin-Angiotensin System Circulation, January 6, 2004; 109(1): 8 - 13. [Full Text] [PDF]
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 L.-J. Min, T.-X. Cui, Y. Yahata, K. Yamasaki, T. Shiuchi, H.-W. Liu, R. Chen, J.-M. Li, M. Okumura, T. Jinno, et al. Regulation of Collagen Synthesis in Mouse Skin Fibroblasts by Distinct Angiotensin II Receptor Subtypes Endocrinology, January 1, 2004; 145(1): 253 - 260. [Abstract] [Full Text] [PDF]
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P. A. Modesti, S. Vanni, I. Bertolozzi, I. Cecioni, C. Lumachi, A. M. Perna, M. Boddi, and G. F. Gensini Different Growth Factor Activation in the Right and Left Ventricles in Experimental Volume Overload Hypertension, January 1, 2004; 43(1): 101 - 108. [Abstract] [Full Text] [PDF]
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 D. Kumar, V. Menon, W. R. Ford, A. S. Clanachan, and B. I. Jugdutt Effect of Angiotensin II lype 2 Receptor Blockade on Activation of Mitogen-Activated Protein Kinases after Ischemia-Reperfusion in Isolated Working Rat Hearts Journal of Cardiovascular Pharmacology and Therapeutics, December 1, 2003; 8(4): 285 - 296. [Abstract] [PDF]
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 K.-L. Hoe, I. Armando, G. Baiardi, T. Sreenath, A. Kulkarni, A. Martianez, and J. M. Saavedra Molecular cloning, characterization, and distribution of the gerbil angiotensin II AT2 receptor Am J Physiol Regulatory Integrative Comp Physiol, December 1, 2003; 285(6): R1373 - R1383. [Abstract] [Full Text] [PDF]
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 H. Kanaide, T. Ichiki, J. Nishimura, and K. Hirano Cellular Mechanism of Vasoconstriction Induced by Angiotensin II: It Remains To Be Determined Circ. Res., November 28, 2003; 93(11): 1015 - 1017. [Full Text] [PDF]
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A. Boldt, U. Wetzel, J. Weigl, J. Garbade, J. Lauschke, G. Hindricks, H. Kottkamp, J. F. Gummert, and S. Dhein Expression of angiotensin II receptors in human left and right atrial tissue in atrial fibrillation with and without underlying mitral valve disease J. Am. Coll. Cardiol., November 19, 2003; 42(10): 1785 - 1792. [Abstract] [Full Text] [PDF]
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Z. Lako-Futo, I. Szokodi, B. Sarman, G. Foldes, H. Tokola, M. Ilves, H. Leskinen, O. Vuolteenaho, R. Skoumal, R. deChatel, et al. Evidence for a Functional Role of Angiotensin II Type 2 Receptor in the Cardiac Hypertrophic Process In Vivo in the Rat Heart Circulation, November 11, 2003; 108(19): 2414 - 2422. [Abstract] [Full Text] [PDF]
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 M. Ruperez, M. Ruiz-Ortega, V. Esteban, O. Lorenzo, S. Mezzano, J. J. Plaza, and J. Egido Angiotensin II Increases Connective Tissue Growth Factor in the Kidney Am. J. Pathol., November 1, 2003; 163(5): 1937 - 1947. [Abstract] [Full Text] [PDF]
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T. Yamada, A. Kuno, K. Masuda, K. Ogawa, M. Sogawa, S. Nakamura, T. Ando, H. Sano, T. Nakazawa, H. Ohara, et al. Candesartan, an Angiotensin II Receptor Antagonist, Suppresses Pancreatic Inflammation and Fibrosis in Rats J. Pharmacol. Exp. Ther., October 1, 2003; 307(1): 17 - 23. [Abstract] [Full Text] [PDF]
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A. Jones, S. S. Dhamrait, J. R. Payne, E. Hawe, P. Li, I. S. Toor, L. Luong, P. T.E. Wootton, G. J. Miller, S. E. Humphries, et al. Genetic Variants of Angiotensin II Receptors and Cardiovascular Risk in Hypertension Hypertension, October 1, 2003; 42(4): 500 - 506. [Abstract] [Full Text] [PDF]
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B. I. Jugdutt Ventricular Remodeling After Infarction and the Extracellular Collagen Matrix: When Is Enough Enough? Circulation, September 16, 2003; 108(11): 1395 - 1403. [Full Text] [PDF]
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A. Gonzalez, M. A Fortuno, R. Querejeta, S. Ravassa, B. Lopez, N. Lopez, and J. Diez Cardiomyocyte apoptosis in hypertensive cardiomyopathy Cardiovasc Res, September 1, 2003; 59(3): 549 - 562. [Abstract] [Full Text] [PDF]
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 K. Ino, C. Uehara, F. Kikkawa, H. Kajiyama, K. Shibata, T. Suzuki, E. E. Khin, M. Ito, M. Takeuchi, A. Itakura, et al. Enhancement of Aminopeptidase A Expression during Angiotensin II-Induced Choriocarcinoma Cell Proliferation through AT1 Receptor Involving Protein Kinase C- and Mitogen-Activated Protein Kinase-Dependent Signaling Pathway J. Clin. Endocrinol. Metab., August 1, 2003; 88(8): 3973 - 3982. [Abstract] [Full Text] [PDF]
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M. A. Fortuno, A. Gonzalez, S. Ravassa, B. Lopez, and J. Diez Clinical implications of apoptosis in hypertensive heart disease Am J Physiol Heart Circ Physiol, May 1, 2003; 284(5): H1495 - H1506. [Full Text] [PDF]
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J.-M. Li and A. M. Shah Mechanism of Endothelial Cell NADPH Oxidase Activation by Angiotensin II. ROLE OF THE p47phox SUBUNIT J. Biol. Chem., March 28, 2003; 278(14): 12094 - 12100. [Abstract] [Full Text] [PDF]
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R. Garg and K. N. Pandey Angiotensin II-Mediated Negative Regulation of Npr1 Promoter Activity and Gene Transcription Hypertension, March 1, 2003; 41(3): 730 - 736. [Abstract] [Full Text] [PDF]
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Y. Oishi, R. Ozono, Y. Yano, Y. Teranishi, M. Akishita, M. Horiuchi, T. Oshima, and M. Kambe Cardioprotective Role of AT2 Receptor in Postinfarction Left Ventricular Remodeling Hypertension, March 1, 2003; 41(3): 814 - 818. [Abstract] [Full Text] [PDF]
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Y. Nakamura, M. Yoshiyama, T. Omura, K. Yoshida, Y. Izumi, K. Takeuchi, S. Kim, H. Iwao, and J. Yoshikawa Beneficial effects of combination of ACE inhibitor and angiotensin II type 1 receptor blocker on cardiac remodeling in rat myocardial infarction Cardiovasc Res, January 1, 2003; 57(1): 48 - 54. [Abstract] [Full Text] [PDF]
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 E. Pantev, E. Stenman, A. Wackenfors, L. Edvinsson, and M. Malmsjo Comparison of the antagonistic effects of different angiotensin II receptor blockers in human coronary arteries Eur J Heart Fail, December 1, 2002; 4(6): 699 - 705. [Abstract] [Full Text] [PDF]
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 F. C. Sasso, O. Carbonara, M. Persico, D. Iafusco, T. Salvatore, R. D'Ambrosio, R. Torella, and D. Cozzolino Irbesartan Reduces the Albumin Excretion Rate in Microalbuminuric Type 2 Diabetic Patients Independently of Hypertension: A randomized double-blind placebo-controlled crossover study Diabetes Care, November 1, 2002; 25(11): 1909 - 1913. [Abstract] [Full Text] [PDF]
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D. Baetz, R. S. Haworth, M. Avkiran, and D. Feuvray The ERK pathway regulates Na+-HCO3- cotransport activity in adult rat cardiomyocytes Am J Physiol Heart Circ Physiol, November 1, 2002; 283(5): H2102 - H2109. [Abstract] [Full Text] [PDF]
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 F. Ryckwaert, P. Colson, E. Andre, P.-F. Perrigault, G. Guillon, and C. Barberis Haemodynamic effects of an angiotensin-converting enzyme inhibitor and angiotensin receptor antagonist during hypovolaemia in the anaesthetized pig Br. J. Anaesth., October 1, 2002; 89(4): 599 - 604. [Abstract] [Full Text] [PDF]
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T.-X. Cui, H. Nakagami, C. Nahmias, T. Shiuchi, Y. Takeda-Matsubara, J.-M. Li, L. Wu, M. Iwai, and M. Horiuchi Angiotensin II Subtype 2 Receptor Activation Inhibits Insulin-Induced Phosphoinositide 3-Kinase and Akt and Induces Apoptosis in PC12W Cells Mol. Endocrinol., September 1, 2002; 16(9): 2113 - 2123. [Abstract] [Full Text] [PDF]
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S. Kim, Y. Izumi, Y. Izumiya, Y. Zhan, M. Taniguchi, and H. Iwao Beneficial Effects of Combined Blockade of ACE and AT1 Receptor on Intimal Hyperplasia in Balloon-Injured Rat Artery Arterioscler Thromb Vasc Biol, August 1, 2002; 22(8): 1299 - 1304. [Abstract] [Full Text] [PDF]
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C. Adamy, P. Oliviero, S. Eddahibi, L. Rappaport, J.-L. Samuel, E. Teiger, and C. Chassagne Cardiac modulations of ANG II receptor expression in rats with hypoxic pulmonary hypertension Am J Physiol Heart Circ Physiol, August 1, 2002; 283(2): H733 - H740. [Abstract] [Full Text] [PDF]
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Z. Yang, C. M. Bove, B. A. French, F. H. Epstein, S. S. Berr, J. M. DiMaria, J. J. Gibson, R. M. Carey, and C. M. Kramer Angiotensin II Type 2 Receptor Overexpression Preserves Left Ventricular Function After Myocardial Infarction Circulation, July 2, 2002; 106(1): 106 - 111. [Abstract] [Full Text] [PDF]
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 O. Lorenzo, M. Ruiz-Ortega, P. Esbrit, M. Ruperez, A. Ortega, S. Santos, J. Blanco, L. Ortega, and J. Egido Angiotensin II Increases Parathyroid Hormone-Related Protein (PTHrP) and the Type 1 PTH/PTHrP Receptor in the Kidney J. Am. Soc. Nephrol., June 1, 2002; 13(6): 1595 - 1607. [Abstract] [Full Text] [PDF]
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O. Lorenzo, M. Ruiz-Ortega, Y. Suzuki, M. Ruperez, V. Esteban, T. Sugaya, and J. Egido Angiotensin III Activates Nuclear Transcription Factor-{kappa}B in Cultured Mesangial Cells Mainly via AT2 Receptors: Studies with AT1 Receptor-Knockout Mice J. Am. Soc. Nephrol., May 1, 2002; 13(5): 1162 - 1171. [Abstract] [Full Text] [PDF]
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A. Goette, U. Lendeckel, and H. U Klein Signal transduction systems and atrial fibrillation Cardiovasc Res, May 1, 2002; 54(2): 247 - 258. [Abstract] [Full Text] [PDF]
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 R. Ferrari, G. Guardigli, G. Cicchitelli, M. Valgimigli, E. Merli, O. Soukhomorskaia, and C. Ceconi Angiotensin II overproduction: enemy of the vessel wall Eur. Heart J. Suppl., February 1, 2002; 4(suppl_A): A26 - A30. [Abstract] [PDF]
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L. Wu, M. Iwai, H. Nakagami, R. Chen, J. Suzuki, M. Akishita, M. de Gasparo, and M. Horiuchi Effect of Angiotensin II Type 1 Receptor Blockade on Cardiac Remodeling in Angiotensin II Type 2 Receptor Null Mice Arterioscler Thromb Vasc Biol, January 1, 2002; 22(1): 49 - 54. [Abstract] [Full Text] [PDF]
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 B. Badzynska, M. Grzelec-Mojzesowicz, L. Dobrowolski, and J. Sadowski Differential effect of angiotensin II on blood circulation in the renal medulla and cortex of anaesthetised rats J. Physiol., January 1, 2002; 538(1): 159 - 166. [Abstract] [Full Text] [PDF]
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Y. Kansui, K. Fujii, K. Goto, and I. Abe Bradykinin Enhances Sympathetic Neurotransmission in Rat Blood Vessels Hypertension, January 1, 2002; 39(1): 29 - 34. [Abstract] [Full Text] [PDF]
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J. L. Segar, G. B. Dalshaug, K. A. Bedell, O. M. Smith, and T. D. Scholz Angiotensin II in cardiac pressure-overload hypertrophy in fetal sheep Am J Physiol Regulatory Integrative Comp Physiol, December 1, 2001; 281(6): R2037 - R2047. [Abstract] [Full Text] [PDF]
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C. Berry, R. Touyz, A. F. Dominiczak, R. C. Webb, and D. G. Johns Angiotensin receptors: signaling, vascular pathophysiology, and interactions with ceramide Am J Physiol Heart Circ Physiol, December 1, 2001; 281(6): H2337 - H2365. [Abstract] [Full Text] [PDF]
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M. P. Schuijt, M. Basdew, R. van Veghel, R. de Vries, P. R. Saxena, R. G. Schoemaker, and A. H. Jan Danser AT2 receptor-mediated vasodilation in the heart: effect of myocardial infarction Am J Physiol Heart Circ Physiol, December 1, 2001; 281(6): H2590 - H2596. [Abstract] [Full Text] [PDF]
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J. Deinum, J. M.G. van Gool, M. J.M. Kofflard, F. J. ten Cate, and A.H. J. Danser Angiotensin II Type 2 Receptors and Cardiac Hypertrophy in Women With Hypertrophic Cardiomyopathy Hypertension, December 1, 2001; 38(6): 1278 - 1281. [Abstract] [Full Text] [PDF]
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M. Ruiz-Ortega, O. Lorenzo, M. Ruperez, V. Esteban, Y. Suzuki, S. Mezzano, J.J. Plaza, and J. Egido Role of the Renin-Angiotensin System in Vascular Diseases: Expanding the Field Hypertension, December 1, 2001; 38(6): 1382 - 1387. [Abstract] [Full Text] [PDF]
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Y. Suzuki, O. Lopez-Franco, D. Gomez-Garre, N. Tejera, C. Gomez-Guerrero, T. Sugaya, R. Bernal, J. Blanco, L. Ortega, and J. Egido Renal Tubulointerstitial Damage Caused by Persistent Proteinuria Is Attenuated in AT1-Deficient Mice : Role of Endothelin-1 Am. J. Pathol., November 1, 2001; 159(5): 1895 - 1904. [Abstract] [Full Text] [PDF]
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D. Henrion, N. Kubis, and B. I. Levy Physiological and Pathophysiological Functions of the AT2 Subtype Receptor of Angiotensin II: From Large Arteries to the Microcirculation Hypertension, November 1, 2001; 38(5): 1150 - 1157. [Abstract] [Full Text] [PDF]
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C.-M. Yu, G. L. Tipoe, K. Wing-Hon Lai, and C.-P. Lau Effects of combination of angiotensin-converting enzyme inhibitor and angiotensin receptor antagonist on inflammatory cellular infiltration and myocardial interstitial fibrosis after acute myocardial infarction J. Am. Coll. Cardiol., October 1, 2001; 38(4): 1207 - 1215. [Abstract] [Full Text] [PDF]
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Y. Shibasaki, H. Matsubara, Y. Nozawa, Y. Mori, H. Masaki, A. Kosaki, Y. Tsutsumi, Y. Uchiyama, S. Fujiyama, A. Nose, et al. Angiotensin II Type 2 Receptor Inhibits Epidermal Growth Factor Receptor Transactivation by Increasing Association of SHP-1 Tyrosine Phosphatase Hypertension, September 1, 2001; 38(3): 367 - 372. [Abstract] [Full Text] [PDF]
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S. Sanada, M. Kitakaze, K. Node, S. Takashima, A. Ogai, H. Asanuma, Y. Sakata, M. Asakura, H. Ogita, Y. Liao, et al. Differential Subcellular Actions of ACE Inhibitors and AT1 Receptor Antagonists on Cardiac Remodeling Induced by Chronic Inhibition of NO Synthesis in Rats Hypertension, September 1, 2001; 38(3): 404 - 411. [Abstract] [Full Text] [PDF]
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S. A. Mezzano, M. Ruiz-Ortega, and J. Egido Angiotensin II and Renal Fibrosis Hypertension, September 1, 2001; 38(3): 635 - 638. [Abstract] [Full Text] [PDF]
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S. Lee, C. M. Kramer, S. Mankad, S.-e. Yoo, and K. Sandberg Combined angiotensin converting enzyme inhibition and angiotensin AT1 receptor blockade up-regulates myocardial AT2 receptors in remodeled myocardium post-infarction Cardiovasc Res, July 1, 2001; 51(1): 131 - 139. [Abstract] [Full Text] [PDF]
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H. Matsubara Renin-Angiotensin System in Human Failing Hearts : Message From Nonmyocyte Cells to Myocytes Circ. Res., May 11, 2001; 88(9): 861 - 863. [Full Text] [PDF]
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M. Ruiz-Ortega, O. Lorenzo, M. Ruperez, J. Blanco, and J. Egido Systemic Infusion of Angiotensin II into Normal Rats Activates Nuclear Factor-{{kappa}}B and AP-1 in the Kidney : Role of AT1 and AT2 Receptors Am. J. Pathol., May 1, 2001; 158(5): 1743 - 1756. [Abstract] [Full Text] [PDF]
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L. H. Opie and M. N. Sack Enhanced Angiotensin II Activity in Heart Failure : Reevaluation of the Counterregulatory Hypothesis of Receptor Subtypes Circ. Res., April 13, 2001; 88(7): 654 - 658. [Abstract] [Full Text] [PDF]
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 A. Otani, H. Takagi, H. Oh, S. Koyama, and Y. Honda Angiotensin II Induces Expression of the Tie2 Receptor Ligand, Angiopoietin-2, in Bovine Retinal Endothelial Cells Diabetes, April 1, 2001; 50(4): 867 - 875. [Abstract] [Full Text]
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S. Fujiyama, H. Matsubara, Y. Nozawa, K. Maruyama, Y. Mori, Y. Tsutsumi, H. Masaki, Y. Uchiyama, Y. Koyama, A. Nose, et al. Angiotensin AT1 and AT2 Receptors Differentially Regulate Angiopoietin-2 and Vascular Endothelial Growth Factor Expression and Angiogenesis by Modulating Heparin Binding-Epidermal Growth Factor (EGF)-Mediated EGF Receptor Transactivation Circ. Res., January 19, 2001; 88(1): 22 - 29. [Abstract] [Full Text] [PDF]
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S. G. Myerson, H. E. Montgomery, M. Whittingham, M. Jubb, M. J. World, S. E. Humphries, and D. J. Pennell Left Ventricular Hypertrophy With Exercise and ACE Gene Insertion/Deletion Polymorphism : A Randomized Controlled Trial With Losartan Circulation, January 16, 2001; 103(2): 226 - 230. [Abstract] [Full Text] [PDF]
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S. Kim, M. Yoshiyama, Y. Izumi, H. Kawano, M. Kimoto, Y. Zhan, and H. Iwao Effects of Combination of ACE Inhibitor and Angiotensin Receptor Blocker on Cardiac Remodeling, Cardiac Function, and Survival in Rat Heart Failure Circulation, January 2, 2001; 103(1): 148 - 154. [Abstract] [Full Text] [PDF]
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S. L. Malendowicz, P. V. Ennezat, M. Testa, L. Murray, E. H. Sonnenblick, T. Evans, and T. H. LeJemtel Angiotensin II Receptor Subtypes in the Skeletal Muscle Vasculature of Patients With Severe Congestive Heart Failure Circulation, October 31, 2000; 102(18): 2210 - 2213. [Abstract] [Full Text] [PDF]
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J. L. Hansen, G. Servant, T. J. Baranski, T. Fujita, T. Iiri, and S. P. Sheikh Functional Reconstitution of the Angiotensin II Type 2 Receptor and Gi Activation Circ. Res., October 27, 2000; 87(9): 753 - 759. [Abstract] [Full Text] [PDF]
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A. J. Allred, M. C. Chappell, C. M. Ferrario, and D. I. Diz Differential actions of renal ischemic injury on the intrarenal angiotensin system Am J Physiol Renal Physiol, October 1, 2000; 279(4): F636 - F645. [Abstract] [Full Text] [PDF]
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Y. Xu, A. S. Clanachan, and B. I. Jugdutt Enhanced Expression of Angiotensin II Type 2 Receptor, Inositol 1,4,5-Trisphosphate Receptor, and Protein Kinase C{epsilon} During Cardioprotection Induced by Angiotensin II Type 2 Receptor Blockade Hypertension, October 1, 2000; 36(4): 506 - 510. [Abstract] [Full Text] [PDF]
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K. Goto, K. Fujii, U. Onaka, I. Abe, and M. Fujishima Renin-Angiotensin System Blockade Improves Endothelial Dysfunction in Hypertension Hypertension, October 1, 2000; 36(4): 575 - 580. [Abstract] [Full Text] [PDF]
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J. P. van Kats, D. J. Duncker, D. B. Haitsma, M. P. Schuijt, R. Niebuur, R. Stubenitsky, F. Boomsma, M. A. D. H. Schalekamp, P. D. Verdouw, and A. H. J. Danser Angiotensin-Converting Enzyme Inhibition and Angiotensin II Type 1 Receptor Blockade Prevent Cardiac Remodeling in Pigs After Myocardial Infarction : Role of Tissue Angiotensin II Circulation, September 26, 2000; 102(13): 1556 - 1563. [Abstract] [Full Text] [PDF]
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 M. de Gasparo, K. J. Catt, T. Inagami, J. W. Wright, and Th. Unger International Union of Pharmacology. XXIII. The Angiotensin II Receptors Pharmacol. Rev., September 1, 2000; 52(3): 415 - 472. [Abstract] [Full Text] [PDF]
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J. Sadoshima Cytokine Actions of Angiotensin II Circ. Res., June 23, 2000; 86(12): 1187 - 1189. [Full Text] [PDF]
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M. Ruiz-Ortega, O. Lorenzo, M. Ruperez, S. Konig, B. Wittig, and J. Egido Angiotensin II Activates Nuclear Transcription Factor {kappa}B Through AT1 and AT2 in Vascular Smooth Muscle Cells : Molecular Mechanisms Circ. Res., June 23, 2000; 86(12): 1266 - 1272. [Abstract] [Full Text] [PDF]
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A. Goette, M. Arndt, C. Rocken, A. Spiess, T. Staack, J. C. Geller, C. Huth, S. Ansorge, H. U. Klein, and U. Lendeckel Regulation of Angiotensin II Receptor Subtypes During Atrial Fibrillation in Humans Circulation, June 13, 2000; 101(23): 2678 - 2681. [Abstract] [Full Text] [PDF]
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W. C. De Mello and A. H. J. Danser Angiotensin II and the Heart : On the Intracrine Renin-Angiotensin System Hypertension, June 1, 2000; 35(6): 1183 - 1188. [Abstract] [Full Text] [PDF]
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