© 1999 American Heart Association, Inc.
Review |
The Cardiac Renin-Angiotensin System
Conceptual, or a Regulator of Cardiac Function?
From The Cardiovascular Research Institute, Division of Molecular Cardiology, The Texas A&M University System Health Science Center, Temple, Tex.
Correspondence to David E. Dostal, PhD, The Cardiovascular Research Institute, Division of Molecular Cardiology, The Texas A&M University System HSC, 1901 S 1st St, Bldg 162, Temple, TX 76504. E-mail ddostal{at}medicine.tamu.edu
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Abstract |
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 Top Abstract IntroductionWhich RAS Components Have...Where Is Cardiac Ang...Regulation of the Cardiac...Regulation of the RAS...In Vitro Evidence for...In Vivo Evidence for...Summary and Future DirectionsReferences |
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Abstract—Angiotensin II, the effector peptide of the renin-angiotensin system, regulates cellular growth in response to developmental, physiological, and pathological processes. The identification of renin-angiotensin system components and angiotensin II receptors in cardiac tissue suggests the existence of an autocrine/paracrine system that has effects independent of angiotensin II derived from the circulatory system. To be functional, a local renin-angiotensin system should produce sufficient amounts of the autocrine and/or paracrine factor to elicit biological responses, contain the final effector (angiotensin II receptor), and respond to humoral, neural, and/or mechanical stimuli. In this review, we discuss evidence for a functional cardiac renin-angiotensin system.
Key Words: renin • angiotensinogen • angiotensin II • cardiac myocyte • cardiac fibroblast
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Introduction |
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TopAbstractIntroductionWhich RAS Components Have...Where Is Cardiac Ang...Regulation of the Cardiac...Regulation of the RAS...In Vitro Evidence for...In Vivo Evidence for...Summary and Future DirectionsReferences |
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Clinical and experimental evidence suggests that angiotensin II (Ang II) has an important role in cardiac and vascular pathology associated with hypertension, coronary heart disease, myocarditis, and congestive heart failure, in addition to effects on volume and electrolyte homeostasis. The circulating renin-angiotensin system (RAS) (Figure 1
) consists of
angiotensinogen (Ao), which is cleaved by renin to form
angiotensin I (Ang I). Ang I is converted to Ang II by
angiotensin-converting enzyme (ACE). Ang II
activates plasma membrane receptors that have been
characterized as AT1 or
AT2, on the basis of binding affinity for
nonpeptide antagonists. Although the RAS is an endocrine
system, heart and several other tissues contain and/or synthesize
components of the system,1 2 3 4 5 6 7 8 9 10 suggesting that locally
produced Ang II regulates/modulates tissue function.
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Which RAS Components Have Been Identified in Cardiac Tissue? |
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TopAbstractIntroductionWhich RAS Components Have...Where Is Cardiac Ang...Regulation of the Cardiac...Regulation of the RAS...In Vitro Evidence for...In Vivo Evidence for...Summary and Future DirectionsReferences |
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Renin
Renin has been detected in cardiac atria, ventricles, and primary cultures of neonatal and adult rat ventricular myocytes (Table 1
).1 4 5 8 9 10
Renin mRNA levels in neonatal and adult cardiac
myocytes5 6 and neonatal fibroblasts isolated from
ventricles5 7 are <1% of the levels reported for
kidney.5 In human, renin mRNA has been detected in the
right atrium, right ventricle, and left atrium, and renin
immunostaining has been detected in the
endothelium and vascular smooth muscle of
coronary arteries and veins, as well as in capillaries of the
myocardium.3 There is not universal agreement
that sufficient renin is produced or is even required for cardiac Ang
II production. The following 2 important questions remain to be
answered. (1) Is myocardial Ang II synthesis totally dependent on renin
activity? (2) If so, what are the sources of myocardial renin? Although
a comparison of signal strengths of renin and Ao mRNA in whole heart
and cultured cardiac cells5 6 indicates that renin is the
least abundant RAS precursor, this does not directly answer the
preceding questions. If renin is the only pathway responsible for Ang I
production, it would be rate limiting, making local renin
synthesis and sequestration the key regulators of cardiac Ang II
synthesis. However, if alternative pathways exist, renin could be a
minor contributor to cardiac Ang II synthesis. Determination of whether
renin is rate limiting cannot be based solely on relative abundance,
because turnover is also important. Because renin is an enzyme, rather
than a substrate, Ao could be the limiting component, if cardiac renin
protein turnover is low. Evidence that renin is rate limiting has been
demonstrated in cultures of neonate rat cardiac
myocytes.11 Overexpression of renin, but not of Ao,
resulted in increased synthesis and release of Ang II.11
However, these data only suggest that conversion of Ao to Ang I is rate
limiting, given that this function could be performed either by renin
or by another enzyme with renin-like activity. It has also been debated
whether local synthesis is the primary source of cardiac renin, because
it can be sequestered from blood.12 This issue has been
difficult to address, given that the cardiac and endocrine RAS are
superimposed. The contribution of local renin synthesis versus that of
sequestration could be addressed if in vivo cardiac Ang I
production were measured in a model lacking 1 of the 2 systems.
One approach would be to use genetic engineering to remove cardiac or
circulating renin, after which cardiac levels of Ang I13
and other RAS components are monitored.
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Angiotensinogen
Ao has been localized in human,14
rat,1 8 and dog15 heart, as well as in
cultured neonatal and adult rat cardiac myocytes6 16 17
and fibroblasts.1 5 7 8 In normal adult human heart,
immunoreactive Ao is primarily distributed in atrial muscle and fibers
of the conduction system, with small amounts in the subendocardial
layer of the ventricle.14 In rat and human heart, the
regional distribution of Ao mRNA is similar to Ao protein. In rat
heart, atrial Ao mRNA levels are at least 10-fold greater than in
ventricles.5 18 In human heart, the concentration of Ao
protein in the left ventricle is 40 pmol/g,12 which is
4% of that in plasma.19 A critical issue is whether
this low level of cardiac Ao has any functional significance. These
measurements were performed using homogenized tissue and do
not account for localized concentrations of Ao in various cellular
compartments (intracellular, interstitial, or plasma
membrane) or anatomical regions of the heart. Low cardiac levels of Ao
may also be indicative of processing to Ang I, which is
consistent with the inverse relationship between cardiac Ao and
renin.12 In transgenic mice, overexpression of Ao by
cardiac myocytes results in increased cardiac Ang II and
ventricular hypertrophy,20 which
suggests that Ao is a limiting component of the cardiac RAS.
Angiotensin-Converting Enzyme
ACE has a heterogeneous distribution in rat heart,
with higher amounts in atria compared with ventricles and higher levels
of ACE binding in the right compared with the left
atrium.21 In this species, dense ACE expression has been
localized in all valves, followed by coronary vessels, aorta,
pulmonary arteries, endocardium, and
epicardium.21 22 However, sinoatrial and
atrioventricular nodes and the remaining portion of the
conduction system contain little ACE.21 In human, ACE
staining has also been localized to the endothelium of
great vessels (aorta and pulmonary artery), but with no
staining in cardiac valves.21 As in rat, ACE is primarily
expressed by human cardiac endothelial cells and
fibroblasts.22 23 24 Cardiac-specific overexpression of ACE
(40- to 100-fold) in transgenic mice results in ultrastructural changes
in the microvascular endothelium and a hypertrophic
pattern of gene expression.25 26 However, the
growth-related effects were much less than in mice with
cardiac-specific overexpression of Ao,20 and cardiac Ang
II was not increased. This suggests that ACE in the mouse is not a
limiting component of the cardiac RAS.
Nonclassical RAS Components
Several serine proteases, such as tonin and cathepsin G, have been
shown to hydrolyze Ang II precursors.27 28 29 30 Recently, an
aspartyl protease with cathepsin D–like properties was shown to
convert Ao to Ang I in adult rat myofibroblasts isolated from
ventricular scar tissue.31 This suggests that
unlike resident cardiac fibroblasts,1 5 7 these
transformed fibroblast-like cells synthesize Ang I via a
non–renin-dependent pathway. However, the actual protease responsible
for Ang I formation in myofibroblasts remains to be determined. It is
unlikely to be cathepsin D, because this enzyme has little activity
above pH 5.0.
Conversion of Ang I to Ang II in human and dog cardiac ventricles may
occur by heart chymase, a chymostatin-sensitive serine
protease.32 33 Unlike ACE, human heart chymase shows high
specificity for Ang I and does not degrade bradykinin or vasoactive
intestinal peptide. Phylogenic evidence34 indicates that
mammalian chymases occur as 2 distinct groups, 
and ß, which
differ in substrate specificity. The -chymases include human, dog,
and rat chymase-3, which convert Ang I to Ang II by cleaving the
Phe8-His9 bond in Ang I (Figure 1
). The Ang II generated is not
further degraded, because the Tyr4-Ile5 bond is resistant to
cleavage by -chymases. The ß-chymases, which include rat chymase-1
and -2 and mouse chymase-1, -2, -3, and -L, are
angiotensinogenases, because these enzymes readily cleave
Tyr4-Ile5 and Phe8-His9 bonds in angiotensins, producing
inactive products. Human chymase has been localized to the cardiac
interstitium and to cytosolic granules of mast,
endothelial, and some mesenchymal
interstitial cells.33 In human and dog heart,
chymase represents 90% of the Ang II–forming capacity of
myocardial extracts, although the role in Ang II formation in intact
heart has not been defined. The observation that ACE levels are highest
in atria, and chymase levels in ventricles, suggests that the relative
contribution of these 2 enzymes to Ang II formation varies within
regions of the human heart. In rat and mouse, heart chymase is
responsible for 5% to 10% of the Ang II–forming activity of
ventricular homogenates.35
Participation of heart chymase in cardiac Ang II formation remains to
be fully assessed using in vivo animal models in molecular and
pharmacological methods.
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Where Is Cardiac Ang II Synthesized? |
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Local production of Ang II could occur by one or more of the following: (1) all RAS components could be synthesized in situ, allowing production of cardiac Ang II to occur independently of the circulation; (2) all RAS components could be taken up from the circulation, and local Ang II would be produced only when these elements are present (in the blood); or (3) a combination of these possibilities.
Ang I and Ang II have been localized in atria and/or ventricles of
dog,36 pig,37 and rat (Table 2).38 39 The presence of
angiotensins in cultured cardiac
myocytes,2 6 40 fibroblasts,2 and
microvascular endothelial cells41 suggests
that these cell types can independently contribute to Ang II
production. Under basal conditions, amounts of Ang II
accumulated in defined media have been reported for cultures of
neonatal rat cardiac myocytes (2.01 fmol/106
cells per 48 hours) and fibroblasts (3.16
fmol/106 cells per 48 hours).2 In
neonatal rat microvascular endothelial cells, a higher
basal secretion rate of 3.16 fmol/106 cells per 5
hours has been reported.41 Although these cells synthesize
Ang II in vitro, the relative contribution of each cell type remains to
be determined in vivo. Interstitial levels of Ang I and Ang
II in dog heart have been shown to be 8122 and 6333 pg/mL,
respectively, which is substantially greater than measurements based on
wet weight36 37 38 39 and >100 times those of
plasma.13 The cardiac interstitial Ang I and
Ang II could arise from the following: (1) intracellular synthesis and
secretion from cardiac cells, (2) extracellular production from
secreted precursors, and (3) intra- or extracellular production
from precursors that are sequestered from the circulation.
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Evidence for Intracellular Ang II Synthesis
Several lines of evidence suggest that intracellular synthesis
accounts for Ang II in cardiac tissue. In isolated perfused rat heart,
tissue levels of Ang II remain constant when
AT1-mediated uptake of Ang II is
blocked.42 Although this observation is consistent
with intracellular Ang II formation, other explanations exist. If
intracellular Ang II is derived from receptor internalization, then
exposure to Ang II receptor antagonist would have little
effect if the internalized peptide is slowly degraded. If intracellular
Ang II synthesis occurs, this process would be expected to take place
in the cytosol and/or secretory vesicles. In support of this concept,
intracellular Ang II and RAS precursors have been localized within
cardiac fibroblasts1 2 7 and myocytes,17 40
similarly to that reported for cell types43 44 45 46
containing a local RAS. In rat juxtaglomerular cells, renin
storage granules contain large amounts of Ang II, consistent
with intracellular production of the
peptide.44 45 46 Electron micrographic evidence suggests the
presence of Ang II in secretory vesicles of neonatal rat
ventricular myocytes.17 Ang II could be
present in either constitutive or regulated secretory vesicles.
Constitutive release of Ang II over 24 to 48 hours by neonatal rat
ventricular myocytes is low,40 but release is
markedly increased by uniaxial stretch,15 17 47 suggesting
a regulated pathway. The mechanotransducer and signaling events leading
to activation of the RAS and secretion of Ang II remain to be
identified.
Sequestration of RAS Components From the Circulatory
System
It has been proposed that a significant portion of cardiac renin
is derived from the circulation. Human renin derived from the
circulation, by the heart or coronary vasculature, results in
long-lasting local Ang II generation.48 High-affinity
binding sites for prorenin and renin have been described in the
heart.48 49 Renin and prorenin are internalized by the
mannose 6-phosphate receptor in neonatal rat cardiac myocytes, and
prorenin is rapidly activated after
internalization.50 In the pig, sequestration of renin and
Ao is responsible for cardiac Ang I and Ang II
production,37 whereas in rat, both sequestration
and local production of precursor appear to be
important.51 Infusion of
125I-labeled Ang I and
125I-labeled Ang II into left ventricles of pig
hearts resulted in steady-state levels that were 5% and 41% of plasma
levels, respectively.52 Accumulation of
125I-labeled Ang II was attenuated by an
AT1 antagonist, indicating that
internalization is the primary mechanism of Ang II cellular uptake in
this species. Regional metabolism and production of
Ang I and Ang II have also been quantified in normal human by utilizing
constant infusions of radiolabeled peptides.53 In contrast
to pig,37 human hearts53 secreted Ang I and
Ang II into the aortic circulation, suggesting that local synthesis is
an important contributor to angiotensin peptide levels.
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Regulation of the Cardiac RAS in the Failing Heart |
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Cardiac Hypertrophy
Volume overload, as a result of aortocaval shunt, is associated with increased expression of renin54 and ACE, but not Ao or AT1, in cardiac ventricles.54 55 This is in contrast to pressure overload of the myocardium, in which there is increased expression of Ao and AT1 mRNA in the left ventricle.56 In hypertrophic human heart, Ao is increased in the subendocardium and has a distribution pattern identical to that of atrial natriuretic peptide (ANP).57 Although ANP is mainly synthesized in atria, ventricular production of ANP increases under conditions of cardiac hypertrophy.57 Under pathologic conditions, Ao and ANP are found in atrial muscle, the conduction system, and the subendocardial layer of the left ventricle of human heart.57 At the molecular level, Ang II stimulates ANP synthesis and release in neonatal rat myocytes,58 and ANP regulates renin and Ao mRNA levels in neonatal cardiac fibroblasts.59 In the latter study,59 activation of the cyclic guanosine monophosphate-coupled receptor was associated with upregulation of renin and Ao mRNA expression. Although cross-regulation between the cardiac RAS and ANP system is intriguing, the functional consequences remain to be determined.
In dog, activities of both ACE and chymase are increased in volume-overloaded left ventricle.60 Unlike ACE, chymase activity in left ventricles did not correlate with left ventricular mass-to-volume ratio or diastolic wall stress, suggesting that ACE has greater physiological relevance under these conditions. Similar results have been shown in humans, in which ACE was increased 3-fold in hearts of patients with chronic heart failure, compared with nonfailing hearts.61 In contrast to dog, no significant difference in chymase gene expression was observed between normal and failing hearts.61 Although these studies suggest a lack of involvement of chymase in pressure-overload hypertrophy, this remains to be confirmed.
Myocardial Infarction
Left ventricular tissue from hearts of patients with
acute and old myocardial infarctions has significantly elevated levels
of renin mRNA.3 In rats, myocardial infarction results in
increased renin mRNA expression in the border zone of infarcted left
ventricle, consistent with a role for intracardiac Ang II in
infarct healing.23 Coronary artery constriction
increased Ao mRNA in noninfarcted regions of the left ventricle but not
in atria or the right ventricle.23 Ao mRNA levels
positively correlated with infarct size, suggesting that increased wall
stress induces Ao mRNA expression. In human, Ao has been identified in
the left ventricle, particularly within cardiac myocytes surrounding
infarcted regions.57
The expression of ACE is increased in left ventricles of patients with coronary artery disease22 and positively correlated with infarct size after coronary artery constriction in rats.62 Infarcted myocardium in human and rat exhibits intense ACE staining within the marginal zone of tissue repair,24 63 with highest levels expressed by endothelial cells associated with sprouting capillaries.63 In human, ACE has also been observed in cardiac myocytes associated with the edge of infarct scar tissue.
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Regulation of the RAS in Cardiac Myocytes and Fibroblasts |
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TopAbstractIntroductionWhich RAS Components Have...Where Is Cardiac Ang...Regulation of the Cardiac...Regulation of the RAS...In Vitro Evidence for...In Vivo Evidence for...Summary and Future DirectionsReferences |
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Glucocorticoids, estrogen, and thyroid hormone markedly increase Ao mRNA levels in whole heart.51 64 In neonatal cardiac fibroblasts, ANP and isoproterenol7 59 are positive regulators of renin and/or Ao mRNA expression (Figure 2
). Negative feedback by Ang II regulates
expression of renin and Ao mRNA in cardiac fibroblasts,7
whereas Ang II upregulates these transcripts in cardiac
myocytes.65 One mechanism by which Ang II upregulates Ao
gene expression in cardiac myocytes is via activation of Janus kinase
(JAK) and signal transducers and activators of
transcription (STAT) proteins. This signal transduction system is
activated by Ang II in isolated cardiac
myocytes66 67 68 69 and acute pressure overload in the
myocardium.70 Ang II–induced activation of
STAT3 and STAT6 increases Ao transcription by binding to the
interferon-
–activated sequence (GAS domain) in the promoter
region of the gene.68 Basal and Ang II–induced activation
of these STAT proteins was shown to be markedly increased in
hypertrophied hearts of spontaneously hypertensive rats, compared with
age-matched normotensive Wistar-Kyoto animals.68 Ang II
released by mechanical stretch has been shown to be responsible for
activation of the JAK/STAT pathway,71 upregulation of Ao
mRNA,72 p53 activation, and apoptosis in cardiac
myocytes.73 Interestingly, p53 activation has been
implicated in upregulation of Ao and AT1 genes in
adult myocytes,73 suggesting that cross-talk occurs
between apoptotic pathways and the local RAS. These studies
provide a compelling argument in favor of JAK/STAT and p53 systems as
important signal transduction pathways involved in regulation of the
RAS in cardiac myocytes. However, the precise mechanisms by which Ang
II activates these signal transduction systems remain to be
determined.
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In Vitro Evidence for a Functional Cardiac RAS |
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TopAbstractIntroductionWhich RAS Components Have...Where Is Cardiac Ang...Regulation of the Cardiac...Regulation of the RAS...In Vitro Evidence for...In Vivo Evidence for...Summary and Future DirectionsReferences |
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Evidence from in vitro studies suggest that the Ang II produced by cardiac tissue can elicit functional responses in the heart. Isolated, perfused hearts from rabbits pretreated with ACE inhibitor demonstrate significant reduction in contractility on pacing,74 suggesting that locally produced Ang II potentiates mechanical activity by altering catecholamine levels at sympathetic nerve terminals. In isovolumic perfused guinea pig hearts, balloon dilatation of the left ventricle stimulated phosphatidylinositol hydrolysis, which was blocked by AT1 antagonist and ACE inhibitor,75 indicating that local Ang II production couples to signal transduction events in isolated cardiac tissue. Blockade of stretch-induced cardiac myocyte hypertrophy by AT1 antagonist or ACE inhibitor40 76 77 suggests that locally produced Ang II is important and can solely mediate cardiac cell growth. However, this does not imply that all cardiac myocyte growth effects are directly mediated by Ang II. For example, cardiac fibroblasts treated with Ang II release a factor that stimulates [3H]leucine incorporation in rat cardiac myocytes,78 which suggests that paracrine mechanisms also contribute to myocyte growth in Ang II–induced cardiac hypertrophy. Also, data from in vitro mechanical stretch studies should be interpreted with caution, because these do not exactly duplicate pressure overload in vivo, a process that requires several days in animals and years in humans.
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In Vivo Evidence for a Functional Cardiac RAS |
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TopAbstractIntroductionWhich RAS Components Have...Where Is Cardiac Ang...Regulation of the Cardiac...Regulation of the RAS...In Vitro Evidence for...In Vivo Evidence for...Summary and Future DirectionsReferences |
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There is evidence to suggest that in vivo humoral activation of the cardiac RAS stimulates cardiac growth. Rats infused with isoproterenol for 7 days had increased plasma and left ventricular levels of Ang II, accompanied by an increase in left ventricular weight and a slight decrease in mean blood pressure.38 Concomitant administration of ACE inhibitor, but not a vasodilator, prevented increases in both left ventricular Ang II content and weight. Although plasma Ang II could contribute to cardiac growth under these conditions, in anephric animals, cardiac Ang II levels and left ventricular hypertrophy were increased, but plasma Ang II levels were low and not changed by isoproterenol. In rats with sympathetic denervation, thyroxine treatment (for 8 weeks) stimulates cardiac hypertrophy, which is associated with increases in cardiac renin activity and mRNA and with Ang II.79 80 Treatment with an AT1 antagonist, but not a calcium channel blocker, markedly attenuated the hypertrophy. This suggests that AT1 blockade prevents hypertrophy, independently of effects on blood pressure and the sympathetic nervous system, and that local production of Ang II mediates hypertrophic effects in this animal model. This conclusion is supported by the observation that cardiac levels of renin and Ang II in nephrectomized animals are increased by thyroxine treatment.79 In the acutely paced dog heart, Ang II induces memory associated with T-wave changes,81 suggesting that the local RAS may also participate in short-term regulation of the heart.
Transgenic Animal Models
Recently, transgenic approaches have been used to determine
whether local activation of the RAS could trigger development of
cardiac hypertrophy.20 Overexpression of the
Ao gene in cardiac myocytes resulted in myocardial
hypertrophy in the absence of hypertension and increased
circulating levels of Ang II. This suggests that Ang II can stimulate
cardiac hypertrophy, independently of
hemodynamic changes. Targeted overexpression of the
AT1 transgene to mouse atrial myocytes resulted
(at birth) in bradycardia and heart block, and in massive enlargement
of the atria caused by myocyte hyperplasia.82 When
AT1 expression was targeted to cardiac ventricles
in transgenic rats,83 the hypertrophic response to
pressure overload was increased compared with control animals,
suggesting that synergism exists between mechanical load and
AT1 activation in induction of cardiac growth.
Targeted overexpression of Ao in hearts of transgenic mice caused
myocyte hypertrophy and fibrosis and resulted in increased
cardiac mass.84 In the mouse, deletion of the Ao gene by
homologous recombination was associated with high mortality by the time
of weaning.85 Together, these results underscore the
importance of the RAS in myocyte growth and electrical conduction in
the heart.
However, not all studies using transgenic animals support a role for Ang II in cardiac growth. In AT1A or AT2 null mice, no abnormal development of the heart was found.86 87 Also, homozygous knockout of the AT1A in the mouse failed to suppress pressure overload–induced cardiac hypertrophy,88 89 although AT1 nonpeptide antagonists have been shown to block this form of cardiac hypertrophy in wild-type mice and rats. A major shortcoming of these studies was the failure to account for contribution of AT1B in the heart by performing receptor binding studies, by administering an AT1 nonpeptide antagonist, or by using a dual-knockout (AT1A/AT1B) transgenic model. It has been shown that Ang II can activate an endogenous AT1B to elicit changes in intracellular calcium in vascular smooth muscle isolated from AT1A knockout mice.90
Tsuchida et al91 have compared phenotypic changes in an AT1A/AT1B dual knockout to those of the Ao gene knockout. Elimination of both AT1A and AT1B results in the same abnormal phenotypes observed in the Ao knockout mouse, but these animals had high plasma levels of Ang II, demonstrating that elimination of both AT1 subtypes is essential for assessing the functional role of AT1. In contrast to Ao knockout mice, some of the dual AT1 knockout animals had severe ventricular septal defects, involving both membranous and muscular portions of the heart, which suggests that the AT1 has an important developmental role in the heart. However, AT1 actions on cardiac development could also involve activation of growth pathways, as well as opposition of growth-inhibitory effects mediated by AT2.
It is also likely that another paracrine or autocrine system can
compensate for actions of the RAS in the AT1
knockout model. On the basis of the number of factors that modulate
growth pathways in cardiac tissue, it is evident that Ang II is but one
component involved in regulation of cardiac growth. With cooperative
interactions among growth factors, elimination of a single humoral
system (eg, Ang II, -adrenergic, endothelin, or cytokine)
with the use of transgenic technology would be expected to fail in
preventing load-induced cardiac hypertrophy. Recently, it
has been shown that mechanical stretch activates growth-related
signal transduction pathways in ventricular myocytes
isolated from both wild-type and Ao null mice.92 93
Stretch-mediated activation of these pathways was blocked by an
AT1 antagonist in myocytes from
wild-type but not Ao knockout mice. Interestingly, a
cytokine-like system was found to substitute for Ang II effects
in myocytes from the Ao knockout mice,93 indicating that
other factors can alternate for cardiac Ang II. In support of this
concept is the observation that in the Gq knockout mouse, there is
incomplete abrogation of hypertrophy in the
pressure-overload model.94 Inability of the Gq knockout to
completely prevent ventricular hypertrophy
indicates that other pathways (eg, other G proteins, tyrosine
kinase–coupled receptors, cytokines, and mechanical force) are
also important. These initial transgenic studies clearly indicate that
more refined genetic approaches will be required to dissect
growth-related mechanisms in the heart. In this regard, it may be
possible to prevent many of the undesired compensatory affects by
designing transgenic animals that have normal expression of the target
gene during embryonic development.
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Summary and Future Directions |
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TopAbstractIntroductionWhich RAS Components Have...Where Is Cardiac Ang...Regulation of the Cardiac...Regulation of the RAS...In Vitro Evidence for...In Vivo Evidence for...Summary and Future DirectionsReferences |
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The concept of an intracardiac RAS, with autocrine and paracrine roles, remains controversial. Work described above provides substantial molecular and biochemical evidence for the presence of a RAS in the heart. All components of the RAS and Ang II receptors (AT1 and AT2) have been identified in cardiac tissue. The synthesis and differential regulatory responses of RAS components to physiological and pharmacological perturbations suggest that the cardiac RAS is functional. However, a number of questions remain to be answered regarding cell types that produce RAS components and the sites and rate-limiting steps of Ang II production in heart. In vivo regulation/metabolism and function of cardiac RAS components at the cellular level in normal and diseased states also remain to be determined. It has become apparent that actions of the RAS are much broader than initially perceived and encompass regulation/modulation of cardiac and coronary vascular function, apoptosis, inflammation, metabolism, and cardiac growth and remodeling.
Development of specific AT1 antagonists has been an important step forward in determining the importance of the RAS. However, the role of the AT2 in cardiac hypertrophy remains to be established. Discovery and utilization of inhibitors of heart chymase will also be necessary in evaluating the importance of nonclassical components in regulation of Ang II production in normal and failing hearts. A positive correlation of RAS component expression with the severity of left ventricular hypertrophy, together with beneficial effects of RAS inhibitors, suggests that cardiac-derived Ang II has a role in mediating myocardial growth. However, distinguishing between local and circulating RAS components represents a major challenge for defining roles in cardiac function. The recent utilization of gene transfer techniques holds promise in addressing these difficult questions. Development of genetic control elements that can be used to direct transgene expression to particular cardiac cell types will be important for elucidating the role of the RAS and determining which components are critical for Ang II production. Although this area of investigative activity has progressed dramatically in the past decade, in the next several years we should be witness to the unraveling of a number of these remaining mysteries.
Received May 14, 1998; accepted July 26, 1999.
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References |
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P. Bridgman, M. A. Aronovitz, R. Kakkar, M. I. Oliverio, T. M. Coffman, W. M. Rand, M. A. Konstam, M. E. Mendelsohn, and R. D. Patten Gender-specific patterns of left ventricular and myocyte remodeling following myocardial infarction in mice deficient in the angiotensin II type 1a receptor Am J Physiol Heart Circ Physiol, August 1, 2005; 289(2): H586 - H592. [Abstract] [Full Text] [PDF]
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R. B. Wichi, S. B. Souza, D. E. Casarini, M. Morris, M. L. Barreto-Chaves, and M. C. Irigoyen Increased blood pressure in the offspring of diabetic mothers Am J Physiol Regulatory Integrative Comp Physiol, May 1, 2005; 288(5): R1129 - R1133. [Abstract] [Full Text] [PDF]
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K. Sekiguchi, X. Li, M. Coker, M. Flesch, P. M Barger, N. Sivasubramanian, and D. L Mann Cross-regulation between the renin-angiotensin system and inflammatory mediators in cardiac hypertrophy and failure Cardiovasc Res, August 15, 2004; 63(3): 433 - 442. [Abstract] [Full Text] [PDF]
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M. Luodonpaa, H. Leskinen, M. Ilves, O. Vuolteenaho, and H. Ruskoaho Adrenomedullin modulates hemodynamic and cardiac effects of angiotensin II in conscious rats Am J Physiol Regulatory Integrative Comp Physiol, June 1, 2004; 286(6): R1085 - R1092. [Abstract] [Full Text] [PDF]
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S. Kinugawa, H. Post, P. M. Kaminski, X. Zhang, X. Xu, H. Huang, F. A. Recchia, M. Ochoa, M. S. Wolin, G. Kaley, et al. Coronary Microvascular Endothelial Stunning After Acute Pressure Overload in the Conscious Dog Is Caused by Oxidant Processes: The Role of Angiotensin II Type 1 Receptor and NAD(P)H Oxidase Circulation, December 9, 2003; 108(23): 2934 - 2940. [Abstract] [Full Text] [PDF]
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J. Piuhola, M. Makinen, I. Szokodi, and H. Ruskoaho Dual role of endothelin-1 via ETA and ETB receptors in regulation of cardiac contractile function in mice Am J Physiol Heart Circ Physiol, June 5, 2003; 285(1): H112 - H118. [Abstract] [Full Text] [PDF]
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K. Shivakumar, D. E. Dostal, K. Boheler, K. M. Baker, and E. G. Lakatta Differential response of cardiac fibroblasts from young adult and senescent rats to ANG II Am J Physiol Heart Circ Physiol, April 1, 2003; 284(4): H1454 - H1459. [Abstract] [Full Text] [PDF]
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A. Kamkin, I. Kiseleva, and G. Isenberg Activation and inactivation of a non-selective cation conductance by local mechanical deformation of acutely isolated cardiac fibroblasts Cardiovasc Res, March 1, 2003; 57(3): 793 - 803. [Abstract] [Full Text] [PDF]
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J. M. Cole, N. Khokhlova, R. L. Sutliff, J. W. Adams, K. M. Disher, H. Zhao, M. R. Capecchi, P. Corvol, and K. E. Bernstein Mice Lacking Endothelial ACE: Normal Blood Pressure With Elevated Angiotensin II Hypertension, February 1, 2003; 41(2): 313 - 321. [Abstract] [Full Text] [PDF]
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J. Piuhola, I. Szokodi, P. Kinnunen, M. Ilves, R. deChatel, O. Vuolteenaho, and H. Ruskoaho Endothelin-1 Contributes to the Frank-Starling Response in Hypertrophic Rat Hearts Hypertension, January 1, 2003; 41(1): 93 - 98. [Abstract] [Full Text] [PDF]
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D. L. Mann Inflammatory Mediators and the Failing Heart: Past, Present, and the Foreseeable Future Circ. Res., November 29, 2002; 91(11): 988 - 998. [Abstract] [Full Text] [PDF]
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M. A. Sussman, A. McCulloch, and T. K. Borg Dance Band on the Titanic: Biomechanical Signaling in Cardiac Hypertrophy Circ. Res., November 15, 2002; 91(10): 888 - 898. [Abstract] [Full Text] [PDF]
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H. L. Li, J. Suzuki, E. Bayna, F.-M. Zhang, E. Dalle Molle, A. Clark, R. L. Engler, and W. Y. W. Lew Lipopolysaccharide induces apoptosis in adult rat ventricular myocytes via cardiac AT1 receptors Am J Physiol Heart Circ Physiol, August 1, 2002; 283(2): H461 - H467. [Abstract] [Full Text] [PDF]
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C. Kumaran and K. Shivakumar Calcium- and superoxide anion-mediated mitogenic action of substance P on cardiac fibroblasts Am J Physiol Heart Circ Physiol, May 1, 2002; 282(5): H1855 - H1862. [Abstract] [Full Text] [PDF]
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W. G. Thomas, Y. Brandenburger, D. J. Autelitano, T. Pham, H. Qian, and R. D. Hannan Adenoviral-Directed Expression of the Type 1A Angiotensin Receptor Promotes Cardiomyocyte Hypertrophy via Transactivation of the Epidermal Growth Factor Receptor Circ. Res., February 8, 2002; 90(2): 135 - 142. [Abstract] [Full Text] [PDF]
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J. P. van Kats, D. Methot, P. Paradis, D. W. Silversides, and T. L. Reudelhuber Use of a Biological Peptide Pump to Study Chronic Peptide Hormone Action in Transgenic Mice. DIRECT AND INDIRECT EFFECTS OF ANGIOTENSIN II ON THE HEART J. Biol. Chem., November 16, 2001; 276(47): 44012 - 44017. [Abstract] [Full Text] [PDF]
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G. Foldes, M. Suo, I. Szokodi, Z. Lako-Futo, R. deChatel, O. Vuolteenaho, P. Huttunen, H. Ruskoaho, and M. Toth Factors Derived from Adrenals Are Required for Activation of Cardiac Gene Expression in Angiotensin II-Induced Hypertension Endocrinology, October 1, 2001; 142(10): 4256 - 4263. [Abstract] [Full Text] [PDF]
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J. Piuhola, A. Hammes, K. Schuh, L. Neyses, O. Vuolteenaho, and H. Ruskoaho Overexpression of sarcolemmal calcium pump attenuates induction of cardiac gene expression in response to ET-1 Am J Physiol Regulatory Integrative Comp Physiol, September 1, 2001; 281(3): R699 - R705. [Abstract] [Full Text] [PDF]
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M. D. Schneider and B. H. Lorell AT2, Judgment Day: Which Angiotensin Receptor Is the Culprit in Cardiac Hypertrophy? Circulation, July 17, 2001; 104(3): 247 - 248. [Full Text] [PDF]
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G. G. Neri Serneri, M. Boddi, L. Poggesi, I. Simonetti, M. Coppo, M. L. Papa, G. F. Lisi, M. Maccherini, R. Becherini, A. Boncompagni, et al. Activation of cardiac renin-angiotensin system in unstable angina J. Am. Coll. Cardiol., July 1, 2001; 38(1): 49 - 55. [Abstract] [Full Text] [PDF]
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P. J Lijnen, V. V Petrov, and R. H Fagard Angiotensin II-induced stimulation of collagen secretion and production in cardiac fibroblasts is mediated via angiotensin II subtype 1 receptors Journal of Renin-Angiotensin-Aldosterone System, June 1, 2001; 2(2): 117 - 122. [Abstract] [PDF]
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F. C. Barone, R. W. Coatney, S. Chandra, S. K. Sarkar, A. H. Nelson, L. C. Contino, D. P. Brooks, W. G. Campbell Jr., E. H. Ohlstein, and R. N. Willette Eprosartan reduces cardiac hypertrophy, protects heart and kidney, and prevents early mortality in severely hypertensive stroke-prone rats Cardiovasc Res, June 1, 2001; 50(3): 525 - 537. [Abstract] [Full Text] [PDF]
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D. T. Dinh, A. G. Frauman, M. Sourial, D. J. Casley, C. I. Johnston, and M. E. Fabiani Identification, Distribution, and Expression of Angiotensin II Receptors in the Normal Human Prostate and Benign Prostatic Hyperplasia Endocrinology, March 1, 2001; 142(3): 1349 - 1356. [Abstract] [Full Text] [PDF]
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D. E. Dostal Regulation of Cardiac Collagen : Angiotensin and Cross-Talk With Local Growth Factors Hypertension, March 1, 2001; 37(3): 841 - 844. [Full Text] [PDF]
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H. Romppanen, J. Puhakka, G. Foldes, I. Szokodi, O. Vuolteenaho, H. Tokola, M. Toth, and H. Ruskoaho Endothelin-1-Independent and Angiotensin II-Independent Induction of Adrenomedullin Gene Expression Hypertension, January 1, 2001; 37(1): 84 - 90. [Abstract] [Full Text] [PDF]
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R. Maruyama, E. Hatta, K. Yasuda, N. C. E. Smith, and R. Levi Angiotensin-Converting Enzyme-Independent Angiotensin Formation in a Human Model of Myocardial Ischemia: Modulation of Norepinephrine Release by Angiotensin Type 1 and Angiotensin Type 2 Receptors J. Pharmacol. Exp. Ther., July 1, 2000; 294(1): 248 - 254. [Abstract] [Full Text]
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S. Eguchi, P. J. Dempsey, G. D. Frank, E. D. Motley, and T. Inagami Activation of MAPKs by Angiotensin II in Vascular Smooth Muscle Cells. METALLOPROTEASE-DEPENDENT EGF RECEPTOR ACTIVATION IS REQUIRED FOR ACTIVATION OF ERK AND p38 MAPK BUT NOT FOR JNK J. Biol. Chem., March 9, 2001; 276(11): 7957 - 7962. [Abstract] [Full Text] [PDF]
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W. G. Thomas, Y. Brandenburger, D. J. Autelitano, T. Pham, H. Qian, and R. D. Hannan Adenoviral-Directed Expression of the Type 1A Angiotensin Receptor Promotes Cardiomyocyte Hypertrophy via Transactivation of the Epidermal Growth Factor Receptor Circ. Res., February 8, 2002; 90(2): 135 - 142. [Abstract] [Full Text] [PDF]
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