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(Circulation Research. 1999;85:643-650.)
© 1999 American Heart Association, Inc.

Review

The Cardiac Renin-Angiotensin System

Conceptual, or a Regulator of Cardiac Function?

David E. Dostal, Kenneth M. Baker

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

	Abstract

Top Abstract Introduction Which 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 Directions References

 
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

	Introduction

Top Abstract Introduction Which 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 Directions References

 
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.

View larger version (24K): [in this window] [in a new window]   Figure 1. The classical RAS. Ao is cleaved by renin between 2 leucines (amino acids 10 and 11) to form the decapeptide Ang I. ACE removes residues 9 and 10 (histidine and leucine) to form the octapeptide Ang II. Removal of aspartic acid from amino acid position 1 by aminopeptidase forms angiotensin III.

	Which RAS Components Have Been Identified in Cardiac Tissue?

Top Abstract Introduction Which 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 Directions References

 
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 myocytes^{5 6} and neonatal fibroblasts isolated from ventricles^{5 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 cells^{5 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.

View this table: [in this window] [in a new window]   Table 1. Localization of Renin-Angiotensin System Components in Cardiac Tissue

Angiotensinogen
Ao has been localized in human,¹⁴ rat,^{1 8} and dog¹⁵ heart, as well as in cultured neonatal and adult rat cardiac myocytes^{6 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.

	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 weight^{36 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.

View this table: [in this window] [in a new window]   Table 2. Measurement of Angiotensins in Cardiac Tissue and Plasma

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 fibroblasts^{1 2 7} and myocytes,^{17 40} similarly to that reported for cell types^{43 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.

	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.

	Regulation of the RAS in Cardiac Myocytes and Fibroblasts

Top Abstract Introduction Which 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 Directions References

 
Glucocorticoids, estrogen, and thyroid hormone markedly increase Ao mRNA levels in whole heart.^{51 64} In neonatal cardiac fibroblasts, ANP and isoproterenol^{7 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 myocytes^{66 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.

View larger version (28K): [in this window] [in a new window]   Figure 2. Putative pathways for humoral and mechanical regulation of angiotensin II production in ventricular cardiac fibroblasts and myocytes. Mechanical stretch stimulates secretion of ANP and angiotensin II (Ang II) from myocytes and increases Ao gene expression in cardiac myocytes and fibroblasts. ANP has paracrine effects on cardiac fibroblasts, resulting in stimulation of renin and Ao synthesis. Norepinephrine, released by sympathetic nerve terminals, activates ß-adrenergic receptors on myocytes and fibroblasts to stimulate renin and Ao synthesis in fibroblasts and Ao synthesis in myocytes. Cathepsins could convert Ao to Ang I directly or indirectly by converting prorenin to renin. Renin binding protein (RBP), expressed on the plasma membrane of myocytes, could also activate prorenin. Extracellular Ang I is converted to Ang II via ACE or chymase. In myocytes, Ang II–mediated stimulation of the AT1 results in activation of JAK2 and STATs to increase Ao gene expression. However, in cardiac fibroblasts, Ang II–induced activation of the plasma membrane AT1 results in feedback inhibition of renin and Ao synthesis.

	In Vitro Evidence for a Functional Cardiac RAS

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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 inhibitor^{40 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.

	In Vivo Evidence for a Functional Cardiac RAS

Top Abstract Introduction Which 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 Directions References

 
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 AT_1A or AT₂ null mice, no abnormal development of the heart was found.^{86 87} Also, homozygous knockout of the AT_1A 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 AT_1B in the heart by performing receptor binding studies, by administering an AT₁ nonpeptide antagonist, or by using a dual-knockout (AT_1A/AT_1B) transgenic model. It has been shown that Ang II can activate an endogenous AT_1B to elicit changes in intracellular calcium in vascular smooth muscle isolated from AT_1A knockout mice.⁹⁰

Tsuchida et al⁹¹ have compared phenotypic changes in an AT_1A/AT_1B dual knockout to those of the Ao gene knockout. Elimination of both AT_1A and AT_1B 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.

	Summary and Future Directions

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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.

	References

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