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Cardiovascular Research 1999 43(4):838-849; doi:10.1016/S0008-6363(99)00145-5
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Copyright © 1999, European Society of Cardiology

The renin–angiotensin system and experimental heart failure

Kai C Wollert* and Helmut Drexler

Department of Cardiology and Angiology, Medizinische Hochschule Hannover, Carl-Neuberg Str. 1, 30625 Hannover, Germany

* Corresponding author. Tel.: +49-511-532-2530; fax: +49-511-532-5412 wollert.kai{at}mh-hannover.de

Received 26 February 1999; accepted 6 April 1999


   Abstract
Top
 Abstract
1 Introduction
 2 Ang II-producing pathways...
 3 Ang II and...
 4 ACE-inhibitors and AT1...
 5 Studies in genetically...
 References
 
Experimental studies suggest that the renin–angiotensin system (RAS) and its primary effector peptide, angiotensin II (Ang II), are involved in the pathophysiology of cardiac hypertrophy and failure. All the components required for Ang II production are present in the heart, and cardiac Ang II formation appears to be regulated independent from the circulating RAS. In animal models and in patients with heart failure, the cardiac RAS is activated and, presumably, local Ang II formation is enhanced. Several cardiac cell types express Ang II type 1 (AT1) and/or type 2 (AT2)-receptors and represent potential targets for Ang II-mediated effects. In neonatal cardiac myocytes, Ang II induces a hypertrophic response via the AT1-receptor. Likewise, activation of the AT1-receptor triggers hypertrophy in terminally differentiated cardiac myocytes and in perfused heart preparations. In the neonatal system, Ang II appears to be a major autocrine/paracrine mediator of cardiac myocyte hypertrophy in response to passive mechanical stretch. By contrast, AT1-receptor activation apparently is not required to trigger load-induced hypertrophy in the adult cardiomyocyte. Recent studies suggest that the AT2-receptor opposes AT1-receptor-mediated growth signals in neonatal and in adult cardiac myocytes. Pharmacological studies have established that a blockade of the RAS at the level of the angiotensin-converting enzyme (ACE) or the AT1-receptor ameliorates the remodeling process of the heart and prolongs long-term survival in animal models of cardiac hypertrophy and failure. The therapeutic effects of ACE inhibitors and AT1-receptor antagonists clearly suggest an important role for the ACE–Ang II–AT1-receptor axis in the development of cardiac hypertrophy and failure. It must be kept in mind, however, that these drugs enhance AT2-receptor and B2-kinin receptor-dependent signaling pathways which may contribute significantly to the beneficial effects observed in vivo. Molecular and physiological analyses of transgenic mice with a cardiac-specific overexpression of the AT1 or AT2-receptor confirm that AT1 and AT2-receptor-dependent signaling cascades potently modulate cardiac myocyte function and growth. However, studies in AT1-receptor knockout mice demonstrate that cardiac hypertrophy in response to hemodynamic overload can occur independent from the AT1-receptor. In this paper, we review recent experimental evidence suggesting a critical role for the RAS in cardiac hypertrophy and failure with special emphasis on the putative role of Ang II and Ang II-receptor signaling in cardiac myocytes.

KEYWORDS Renin–angiotensin system; Heart failure; Cardiac hypertrophy; Myocytes


   1 Introduction
Top
 Abstract
 1 Introduction
2 Ang II-producing pathways...
 3 Ang II and...
 4 ACE-inhibitors and AT1...
 5 Studies in genetically...
 References
 
Cardiac hypertrophy is an important compensatory mechanism of the heart in response to chronic increases in hemodynamic load. Although myocardial hypertrophy initially allows to maintain cardiac function, sustained hemodynamic overloading eventually causes a transition from compensatory hypertrophy to heart failure, characterized by chamber dilatation, progressive contractile dysfunction and impaired survival [1]. Considerable research efforts have focussed on the molecular mechanisms that transduce hemodynamic load into myocardial growth, and that may be responsible for the transition to terminal heart failure. In this context, experimental studies in cell culture systems, animal models and in patients indicate that the RAS and its primary effector peptide, Ang II, are involved in the pathophysiology of cardiac hypertrophy and failure. The Ang II hypothesis is based on four main observations: (1) Ang II is produced locally within the myocardium, (2) the RAS is activated in the hypertrophied and failing heart, (3) Ang II potently modulates cardiac myocyte growth in vitro, and (4) pharmacological blockade of the RAS is highly effective in animal models and in patients with cardiac hypertrophy and failure.


   2 Ang II-producing pathways in the normal, hypertrophied and failing myocardium
Top
 Abstract
 1 Introduction
 2 Ang II-producing pathways...
3 Ang II and...
 4 ACE-inhibitors and AT1...
 5 Studies in genetically...
 References
 
Traditionally, the RAS has been viewed solely as a circulating system involved in the regulation of blood pressure and salt and fluid homeostasis [2]. According to this concept, the kidney releases renin and its inactive precursor prorenin into the circulation. Liver-derived angiotensinogen is then cleaved by renin in the circulating blood to form Ang I. ACE, located on the luminal side of the vascular endothelium, finally converts Ang I to the biologically active octapeptide Ang II, which promotes vasoconstriction and aldosterone release (Fig. 1). This classic concept has undergone important changes, because accumulating evidence indicates that the components of the RAS are synthesized in many tissues, and that tissue Ang II levels can be controlled independent from the circulating RAS. In fact, renin, angiotensinogen, ACE and angiotensin receptors are present in the heart, suggesting that Ang II synthesized locally within the myocardium may be an autocrine/paracrine modulator of cardiac function and structure [3,4].


Figure 1
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  		Fig. 1 Schematic representation of the renin–angiotensin and kallikrein–kinin systems. ACE, angiotensin-converting enzyme; NEP, neutral endopeptidase; PE, prolyl endopeptidase; AT1 and AT2, angiotensin II type 1 and type 2 receptors; BK2, B2-kinin receptor; ACE-I, ACE-inhibitors; AT1-RA, AT1-receptor antagonists. See text for details.

 
Although cardiac renin mRNA expression is extremely low, renin activity is readily detectable in the heart [5]. Studies in nephrectomized pigs have revealed that most, if not all, renin in the heart is derived from the kidney, and actively taken up from the circulation [6]. Renin-uptake has also been demonstrated in normal and failing human hearts [7]. It has been postulated that renin-uptake is mediated by binding of circulating renin to cell membranes in the heart, possibly via an interaction with renin-binding proteins [7–9]. In patients with end-stage heart failure receiving ACE-inhibitor therapy and displaying increased circulating levels of renin, cardiac renin concentration is increased as well and directly correlated with plasma renin levels, suggesting enhanced uptake from the circulation [7]. Interestingly, cardiac angiotensinogen levels in these patients are reduced and are inversely correlated with cardiac renin levels, suggesting enhanced cleavage of angiotensinogen and an increased local production of Ang I in the failing human heart [7]. Increased expression of renin mRNA has been detected in the borderzone of the infarcted left ventricle in rats, indicating that cardiac renin expression may be induced under pathological conditions [10].

In contrast to renin, angiotensinogen appears to be synthesized locally within the myocardium [11–14]. Under physiological conditions, however, cardiac angiotensinogen expression levels are rather low, as indicated by experiments in isolated perfused rat hearts which demonstrate that the heart produces little Ang I unless renin and angiotensionogen are added to the perfusion fluid [15]. However, in rats with chronic pressure overload and in rats with left ventricular failure early after coronary artery ligation or following tachypacing, cardiac angiotensinogen gene expression is enhanced, suggesting that the local generation of angiotensinogen within the myocardium may become more important during cardiac hypertrophy and failure [11,13,16].

Many studies have indicated that the angiotensin-converting enzyme is present within the myocardium. In the normal heart of rats and humans, ACE expression is confined almost exclusively to the endothelial cells of coronary arteries, arterioles and capillaries [17]. Myocardial expression of ACE is increased in rats with pressure overload ventricular hypertrophy and in the viable myocardium following experimental myocardial infarction [18–21]. Moreover, ACE has been shown to be upregulated in the myocardium of patients with end-stage heart failure, regardless of the etiology, i.e. in patients with ischemic as well as with idiopathic dilated cardiomyopathy [22]. In the hypertrophied or failing ventricle, endothelial cells continue to be a major site of cardiac ACE expression, but ACE expression becomes detectable in other cell types as well [17,23–25]. For example, after coronary artery ligation in rats, ACE is markedly increased within the infarct scar and in areas of fibrous tissue formation remote from the site of infarction [23]. Likewise, increased ACE activity has been detected in left ventricular aneurysms of patients after myocardial infarction [24]. A report from the same group indicated that ACE was expressed in fibroblasts, macrophages and endothelial cells present in the scar tissue and in cardiac myocytes in the region adjacent to the infarct scar [25].

Only a few studies have addressed the critical question, whether enhanced cardiac expression of ACE actually promotes an increased production of Ang II. By using isolated, perfused hearts from normal rats and rats with pressure overload hypertrophy, Schunkert and co-workers [18,26] demonstrated that the upregulation of ACE in the hypertrophied left ventricle is associated with an increased intracardiac conversion of Ang I to Ang II.

Several groups have challenged the notion that ACE represents the major Ang II-forming enzyme in the human heart. Urata and co-workers [27,28] demonstrated that ACE-inhibitors could block only 10–20% of total Ang I to Ang II conversion in left ventricular membranes prepared from human hearts. The remaining activity was blocked by a serine protease inhibitor, pointing to chymase as an ACE-bypassing enzyme. In agreement with these early data, Wolny et al. [29], employing a similar method to prepare cardiac membranes, concluded that a chymase-like enzyme is the major Ang I-converting activity in human hearts. In contrast with these results, Zisman et al. [30] reported that the ACE-inhibitor enalapril could inhibit 85% of Ang I-conversion in solubilized human cardiac membranes. However, the membrane preparation technique employed is this study has been criticized, as it may have led to a loss of chymase activity [29,31]. Chymase-like immunoreactivity is found primarily in the extracellular matrix of the heart, with cardiac mast cells, endothelial cells and mesenchymal interstitial cells being the predominant cellular sites of chymase synthesis and storage [32]. It is believed that chymase must be actively secreted by these cell types, before chymase-mediated conversion of Ang I can take place [32]. Therefore, studies using cardiac membrane preparations may overestimate chymase-driven Ang I conversion, because chymase-containing mast cell granules are disrupted during tissue preparation. In fact, in the intact human heart, ACE has been shown to be the predominant Ang II-forming enzyme, at least across the coronary circulation [30]. Moreover, protease inhibitors (e.g. {alpha}1-antitrypsin) present in the interstitial fluid potently inhibit chymase activity, and it has therefore been postulated that, also in the cardiac interstitium, Ang II formation may primarily be regulated by ACE rather than chymase [31]. Clearly, more research is needed to elucidate the pathophysiological triggers that may cause cardiac mast cell activation and chymase release in vivo. In this regard, a recent study has demonstrated that myocardial ischemia represents a potent stimulus for mast cell degranulation [33]. With regard to the failing human heart, there appears to be no induction of chymase mRNA or enzyme activity as compared to nonfailing hearts [22,32].

In summary, all the components required for Ang II production are present in the heart. In fact, it has been shown that most Ang I found in cardiac tissue is synthesized in situ, and that most of the cardiac Ang II is produced by the conversion of locally produced, rather than blood-derived, Ang I [34]. More importantly, there is now convincing evidence that the cardiac RAS is capable of regulating Ang II levels locally within the myocardium, independent from systemic Ang II generation [35,36]. It is therefore critical to identify the cells types in the myocardium that actually express Ang II receptors and represent potential targets for Ang II-mediated effects.

Ang II receptors belong to the large family of seven transmembrane receptors, and have been divided into two pharmacologically distinct types, designated type 1 (AT1) and type 2 (AT2) [37,38]. In rodents, two AT1-receptor subtypes, designated AT1A and AT1B, have been identified. The AT1A and AT1B-receptor subtypes are encoded by distinct genes, but share a 96% homology at the amino acid level [39]. Due to the lack of discriminatory pharmacological antagonists, distinct functions of the two AT1-receptor subtypes have not been defined. On the mRNA level, the AT1A-receptor subtype is much more abundant than the AT1B-receptor subtype in most tissues, including the heart [40,41]. Radiolabeled Ang II-binding assays have suggested, that both AT1- and AT2-receptors are present in adult rat ventricular myocardium, with the AT1-receptor accounting for about 50–70% of specific Ang II binding [42–44]. Ang II-binding assays in isolated cardiomyocytes and in cardiac fibroblasts from adult rat heart indicate that both cell types express the AT1-receptor exclusively [45–47]. AT1-receptor density on rat cardiac myocytes appears to be rather low, however, and some authors have failed to detect Ang II receptors in isolated cardiomyocytes from normal rat hearts [48]. AT2-receptor expression in the myocardium and in coronary vessels has recently been confirmed by immunohistochemistry [49], and reverse transcription polymerase chain reaction [41]. AT2-receptor expressing cell types in the heart remain poorly characterized, however, but may include coronary endothelial cells [49] and, as suggested by some authors, cardiac fibroblasts [50,51]. Several studies, however, have questioned whether there is any significant AT2-receptor expression in adult rat heart. In fact, in situ hybridization and sensitive poly(A)+-Northern blot analyses failed to identify AT2-receptor mRNA expression in adult rat myocardium, whereas AT1-receptor mRNA was readily detectable [37,38,52]. The discordant results with regard to AT2-receptor expression in adult heart make it difficult to obtain a coherent picture at the present time [52].

A number of studies indicate that Ang II receptor expression in the heart is altered in animal models of ventricular hypertrophy and failure. Suzuki et al. [43] demonstrated that left ventricular AT1 and AT2-receptor densities and AT1A-receptor mRNA levels are increased in rats with renovascular or spontaneous hypertension. Rats with cardiac hypertrophy due to aortic banding, however, exhibit a decrease in total cardiac Ang II binding sites associated with a receptor subtype redistribution, i.e. a shift towards a preponderance of the AT2-receptor [44]. Employing RT-PCR analyses, Nio et al. [41] reported that AT1A and AT2-receptor mRNA expression is upregulated in the infarcted and noninfarcted portions of the left ventricle following coronary ligation in the rat. Unfortunately, the cell types expressing AT1 and AT2-receptors were not identified in that study. In this regard, Meggs et al. [45] demonstrated that cardiac myocytes isolated from rats with post-infarction left ventricular failure exhibit an increase in AT1-receptor density, which may be associated with an enhanced susceptibility to Ang II in vitro. In the same study it was shown that hypertrophied myocytes, like myocytes from control hearts, do not express AT2-receptor binding sites [45]. In apparent contrast to the infarct model, cardiac AT1A and AT1B-receptor mRNA expression is unchanged in rats with aortocaval shunt and left ventricular failure [14]. The pathophysiological mechanisms underlying the distinct patterns of AT1 and AT2-receptor regulation in different animal models are largely unknown. Certainly, we need a better understanding of the molecular mechanisms controlling Ang II receptor abundance in different cardiac cell types. In this regard, it has been suggested that the AP-1 and GATA-4 DNA-recognition sequences in the promotor region of the AT1A-receptor are involved in the load-dependent regulation of AT1A-receptor expression in rat cardiac myocytes in vivo [53].

Several groups have investigated Ang II receptor regulation in human heart failure [51,54–56]. By using standard-calibrated RT-PCR analysis, Haywood et al. [56] demonstrated that AT1-receptor mRNA expression is reduced, whereas AT2-receptor mRNA expression is unchanged in failing human hearts. A similar conclusion was reached by Asano et al. [55], who analysed the binding of radiolabeled Ang II to cardiac membranes prepared from terminally failing and control hearts: in the failing heart, AT1-receptor density was downregulated, whereas AT2-receptor density was unaltered. Moreover, in situ RT-PCR in sections of failing and nonfailing ventricles indicated that AT1-receptor mRNA was present in both myocytes and the interstitium [55]. It should be noted however, that the total number of Ang II binding sites in the human ventricle appears to be quite low, i.e. only approximately 10% of the total number of β-adrenergic binding sites [55]. In contrast to these previous studies [55,56], Tsutsumi et al. [51] recently reported that AT2-receptor binding sites and mRNA expression are increased in patients with dilated cardiomyopathy. Interestingly, the enhanced expression of the AT2-receptor was associated with a substantial increase in the expression levels of extracellular matrix genes, and cardiac fibroblasts in the interstitial space were found to be the major AT2-receptor expressing cell type in the failing hearts [51]. It is not known whether the changes in receptor density contribute to, or compensate for the deterioration in human heart failure or whether they simply represent an epiphenomenon. Moreover, it remains to be determined whether the changes in receptor subtype density in the failing heart result in an altered response to Ang II. Conceivably, downregulation of the AT1-receptor in human heart failure may result in an increase in available Ang II levels, and AT2-receptor-mediated effects may become more evident [57].

Ang II has long been recognized as the major inducer of aldosterone synthesis in the adrenal glands. More recent data indicate that aldosterone may also be formed locally within the heart, and that cardiac aldosterone synthesis is enhanced by Ang II [58]. By causing Na+ absorption as well as K+ and Mg2+ excretion in the kidneys, aldosterone promotes water retention and contributes to electrical instability in heart failure. In addition, aldosterone has been shown to modulate the phenotype of cardiac fibroblasts and, potentially, cardiac myocytes through an interaction with the mineralocorticoid receptor in these cell types [59,60]. In cultured cardiac fibroblasts, aldosterone promotes type I collagen mRNA and protein synthesis [59]. In neonatal cardiac myocytes, aldosterone stimulates protein accumulation, suggesting a hypertrophic effect [60]. The pathophysiological significance of aldosterone in heart failure is highlighted by the results of the recent Randomized Aldactone Evaluation Study (RALES). In this study, treatment with an aldosterone antagonist on top of ACE inhibitors and loop diuretics, significantly reduced all cause mortality in patients with symptomatic heart failure [61].


   3 Ang II and load-induced phenotype changes in cardiac myocytes
Top
 Abstract
 1 Introduction
 2 Ang II-producing pathways...
 3 Ang II and...
4 ACE-inhibitors and AT1...
 5 Studies in genetically...
 References
 
Our current knowledge regarding the signal transduction pathways and the biological effects of Ang II in cardiac myocytes has primarily been obtained from a cell culture model employing ventricular cardiac myocytes from neonatal rats. Both AT1- and AT2-receptor are expressed in neonatal cardiac myocytes (i.e. in cultures containing 5–10% of cardiac fibroblasts), accounting for about 60 and 40% of specific Ang II binding respectively [62,63]. Stimulation of neonatal cardiomyocytes with Ang II induces the transcription of proto-oncogenes (such as c-fos, c-jun, c-myc and Egr-1), the reactivation of a fetal program of cardiac gene expression (i.e. the induction of ANP, skeletal {alpha}-actin, and β-myosin heavy chain), an enhanced synthesis of growth factors, including platelet-derived growth factor and transforming growth factor-β, and a decreased expression of the Na+/Ca2+-exchanger and sarcoplasmic reticulum Ca2+-ATPase [64,65]. Moreover, Ang II enhances total protein accumulation, promotes the formation of new myofibrils, and induces an increase in cell size. Apparently, all of these effects are mediated by the AT1-receptor [64]. More recent studies have indicated that the effects of Ang II on protein accumulation are potentiated in the presence of selective AT2-receptor antagonists, suggesting that the AT2-receptor may inhibit AT1-receptor-mediated hypertrophy in neonatal cardiomyocytes [66,67]. Collectively, the molecular and morphological alterations induced by Ang II in neonatal cardiomyocytes mimic the changes that can be observed in hemodynamic overload-induced cardiac hypertrophy in the in vivo situation. Neonatal cardiac myocytes have therefore been used as a valuable in vitro model to dissect the molecular mechanisms that couple the AT1-receptor to the activation of the hypertrophic response.

Multiple signal transduction pathways are activated in response to AT1-receptor stimulation (reviewed in Ref. [68]). The AT1-receptor transactivates phospholipases C and D, resulting in phosphatidylinositol hydrolysis and the activation of the diacylgylycerol-regulated isoforms of protein kinase C (PKC) [69]. Moreover, Ang II acting via the AT1-receptor activates p21ras, Raf-1 kinase and mitogen-activated protein kinases (MAPK), i.e. extracellular signal-regulated kinase (ERK)1 and ERK2 and c-Jun N-terminal kinase(s) [64,70–73]. Finally, Ang II stimulates tyrosine phosphorylation of the Janus kinases JAK2 and Tyk2, resulting in an activation of the latent transcription factors STAT1, STAT2 and STAT5 in neonatal cardiomyocytes [74,75]. It remains largely unknown how these distinct signaling pathways promote the molecular and morphological features of the hypertrophic response. In this regard, activation of phospholipases and PKC appears to play an essential role in the Ang II-mediated induction of c-fos [69], whereas 70-kDa S6 kinase seems to be required for Ang II-enhanced protein accumulation [76]. More recently, activation of the small G-protein, RhoA, has been shown to be involved in myofibril formation by Ang II [77], and reactive oxygen species were found to be critical for Ang II-induced protein accumulation in neonatal cardiomyocytes [78].

It has been questioned whether the effects of Ang II in neonatal cardiomyocyte culture are mediated via a direct interaction of Ang II with the AT1-receptor on neonatal cardiomyocytes [79,80]. For example, Harada et al. [80] demonstrated that Ang II does not promote an increase in ANP production and cell size in highly purified neonatal cardiomyocytes. However, upon inclusion of even a small percentage (5%) of nonmyocytes (mostly fibroblasts) in the culture system, Ang II readily induced cardiomyocyte hypertrophy. In the same study [80], Ang II induced endothelin-1 secretion from nonmyocytes, and the hypertrophic effect of Ang II in myocyte–nonmyocyte cocultures was partially blocked by an ET-A receptor antagonist. The hypertrophic effects of Ang II in neonatal cardiomyocytes may therefore depend, at least in part, on the release of endothelin-1 and additional as yet unknown paracrine factors from nonmyocytes present in the cell culture system.

Neonatal cardiac myocytes have also been used as a cell culture model to study the mechanisms whereby external load is converted into intracellular growth signals (reviewed in Ref. [81]). In this cell system, passive mechanical stretch activates a hypertrophic response that is very similar to growth factor-induced cardiomyocyte hypertrophy [82,83]. Several second messenger systems are activated in response to mechanical stretch, including PKC, p21ras, Raf-1 kinase, ERK and JNK mitogen-activated protein kinases [84–87]. Mechanical stretching increases angiotensinogen mRNA levels and upregulates the number of AT1- and AT2-receptor binding sites in neonatal cardiac myocyte cultures [63,88]. More importantly, stretch causes the release of Ang II from neonatal cardiac myocytes, suggesting that Ang II may act as a mediator of stretch-induced hypertrophy [89]. Indeed, stretch-induced activation of ERKs, protooncogene expression and protein accumulation are inhibited by AT1-receptor blockade [89]. However, AT1-receptor antagonists only partially blunt the hypertrophic response to mechanical stretch, indicating that Ang II-independent mechanisms (secretory and/or non-secretory) are involved, as well [84,90,91]. In fact, certain signaling pathways, e.g. JNK, are activated by stretch without the participation of Ang II [87]. Moreover, studies employing neonatal cardiomyocytes from angiotensinogen and AT1A-receptor knockout mice have revealed that Ang II-AT1-receptor signaling is dispensable for the stretch-induced activation of ERKs [92,93]. In line with these observations, endothelin-1 been shown to be released from neonatal cardiomyocytes in response to mechanical stretch and to promote hypertrophy in synergy with Ang II, and cytokines signaling through the gp130-receptor have been implicated in the stretch-induced activation of ERKs [94,95]. Finally, activation of the Na+/H+-exchanger by Ang II-dependent and Ang II-independent pathways has recently been shown to play a critical role in stretch-induced hypertrophy of neonatal cardiomyocytes [96,97].

Several studies have examined the effects of Ang II on isolated, terminally differentiated adult cardiomyocytes. Ang II-stimulation of adult ventricular cardiomyocytes isolated from rabbit or rat has been shown to stimulate Na+/H+-exchange, resulting in an intracellular alkalinization and an increase in the amplitude of cell contraction [98,99]. Remarkably, Ang II does not increase Na+/H+-exchange and cell contraction amplitude in hypertrophied myocytes isolated from rats following aortic banding [99]. In contrast to these results, that suggest a positive inotropic effect of Ang II, at least on nonfailing, rodent cardiomyocytes, other investigators have not been able to detect any significant effects of Ang II on the contraction characteristics of adult cardiomyocytes from normal guinea pig or rat hearts [100]. The reason(s) for these discrepant results are not clear. With regard to the human heart, Ang II does not appear to promote a direct positive inotropic effect on isolated cardiac myocytes and muscle-strip preparations from human left ventricle [100,101].

Mechanical stretch has been shown to enhance gene expression and protein accumulation in isolated adult ventricular cardiomyocytes, indicating that an increase in external load is a sufficient stimulus for the activation of a hypertrophic response in adult cardiomyocytes, as well [102,103]. Although prolonged stimulation of adult cardiac myocytes with Ang II promotes a modest increase in protein synthesis via the AT1-receptor [104,105], the increase in protein synthesis in response to mechanical stretch appears to be mediated by Ang II-independent mechanisms [103]. Interestingly however, stretch-induced expression of the protooncogene c-fos can be blocked by a competitive peptide to Ang II, indicating a requirement for Ang II at least for this early response to passive load [103]. In a recent study, Ang II was shown to induce the expression of the MAPK-phosphatase MKP-1 through the AT2-receptor in adult cardiac myocytes [106]. Although this observation appears to contradict earlier reports that failed to detect significant AT2-receptor expression in cultured adult rat cardiomyocytes [45,47], it raises the intriguing possibility that Ang II may promote growth-inhibiting effects in cardiac myocytes via AT2-receptor stimulation [106].

Studies in isovolumic perfused beating rat heart preparations, support the conclusion that load-induced hypertrophy in adult cardiac myocytes can occur independent from the AT1-receptor. In this model, Ang II as well as acute increases in systolic wall stress promote a marked stimulation of total protein synthesis [107,108]. The hypertrophic response to Ang II is completely abolished by AT1-receptor blockade, indicating that the AT1-receptor mediates the trophic effects of Ang II [108]. By contrast, AT1-receptor antagonism does not prevent the growth response to acute pressure overload [109]. Interestingly, the increase in protein synthesis in response to Ang II is blunted in hypertrophied hearts from rats with ascending aortic stenosis [107]. Earlier studies have demonstrated that a redistribution of angiotensin receptor subtypes occurs in these hearts, resulting in a preponderance of the AT2-receptor [44]. Intriguingly, perfusion of hypertrophied hearts with Ang II and a specific AT2-receptor antagonist restores the growth promoting effects of Ang II, indicating that the upregulation of the AT2-receptor in pressure overload hypertrophy blunts the growth response to Ang II [110].

A report from Anversa’s group [111] has demonstrated that mechanical stretch promotes Ang II release and apoptosis in adult rat cardiac myocytes in vitro, and that AT1-receptor blockade prevents apoptosis in this setting, suggesting a critical role for Ang II. Indeed, in a study from the same lab, Ang II was shown to induce apoptosis in cultured adult rat cardiac myocytes via the AT1-receptor [112]. It has been postulated that ongoing cardiomyocyte dropout by apoptosis contributes to the progression of compensatory cardiac hypertrophy to overt heart failure, and that an increase in ventricular wall stress represents a potential trigger mechanism for apoptosis in the heart [113]. Therefore, the observation that Ang II can mediate stretch-induced cardiac myocyte apoptosis may be of clinical relevance.


   4 ACE-inhibitors and AT1-receptor antagonists in experimental heart failure
Top
 Abstract
 1 Introduction
 2 Ang II-producing pathways...
 3 Ang II and...
 4 ACE-inhibitors and AT1...
5 Studies in genetically...
 References
 
ACE inhibitors favorably alter hemodynamics, improve symptoms and reduce overall mortality in patients with congestive heart failure (reviewed in Ref. [114]). A recent clinical trial suggests that AT1-receptor antagonists reduce mortality in heart failure patients as well [115]. The therapeutic efficacy of ACE inhibition and AT1-receptor blockade has been viewed as strong evidence for a critical involvement of the RAS in the pathophysiology of congestive heart failure. However, ACE inhibitors and AT1-receptor antagonists promote important biological effects beyond the inhibition of Ang II formation or the interference with Ang II at the AT1-receptor level (Fig. 1). ACE acts as a potent kinin-degrading enzyme, and, accordingly, plasma and tissue kinin levels are increased by ACE inhibitors [116–118]. During AT1-receptor blockade, plasma Ang II levels increase which may promote an enhanced activation of the AT2-receptor [119]. Importantly, in certain cell types, activation of the AT2-receptor triggers kinin generation and nitric oxide production, suggesting that AT1-receptor antagonists may enhance kinin-mediated effects [120]. Therefore, the therapeutic effects of ACE inhibitors and AT1-receptor antagonists may not be depend solely on the interference with the ACE–Ang II–AT1-receptor pathway, but may also relate to kinin potentiation and augmentation of AT2-receptor-mediated effects. Importantly, depending on the animal model or the endpoint studied, the mechanisms of action of ACE inhibitors and AT1-receptor antagonists can differ significantly. The following discussion focusses on two distinct rat models of cardiac hypertrophy/failure induced by myocardial infarction (MI) and ascending aortic stenosis.

As demonstrated in seminal studies from Pfeffer’s group [121,122], ligation of the left coronary artery in rats promotes profound alterations of ventricular architecture, characterized by an early expansion of the infarcted area, hypertrophy of the surviving myocardium, progressive dilatation of the left ventricle, and- depending on the size of the infarct, frank cardiac failure. Soon thereafter, Pfeffer and co-workers [123,124] realized that chronic ACE inhibition attenuates cardiac hypertrophy and chamber dilatation and improves long-term survival in the rat infarct model. Conceivably, the therapeutic effects of ACE inhibitors may be related to an inhibition of the circulating RAS and may simply reflect afterload reduction. However, the beneficial effects of ACE inhibition may also result from an inhibition of the tissue RAS, which is selectively activated in the heart and kidneys following infarction [20,21]. To assess the significance of afterload reduction and plasma vs. tissue ACE inhibition for the beneficial effects of ACE inhibitors, we compared low-dose and high-dose ACE inhibition in post MI rats. High-dose ACE inhibition, characterized by a sustained reduction of arterial blood pressure and inhibition of tissue ACE reduced cardiac hypertrophy and long-term mortality. By contrast, chronic low-dose ACE inhibition, although exerting a significant inhibition of plasma and pulmonary ACE, did not reduce arterial blood pressure, cardiac hypertrophy and mortality [21]. Therefore, unloading of the ventricle and/or inhibition of ACE within tissues appear to be critical for the beneficial effects of ACE inhibitors. As shown in recent studies, investigating combined ACE inhibition and B2-kinin receptor blockade in the rat infarct model, kinins appear to contribute to the reduction of interstitial myocardial fibrosis by ACE inhibitors [125,126]. By contrast, the attenuation of cardiomyocyte hypertrophy by ACE inhibitors is mediated by kinin-independent mechanisms, suggesting that this effect is related instead to a reduction of Ang II formation [125]. In line with this conclusion, myocardial Ang II levels have been shown to be decreased significantly during chronic ACE inhibition in post MI rats [125,127]. However, alternative mechanisms need to be considered as well. During chronic ACE inhibition, plasma renin increases and promotes enhanced Ang I formation from angiotensinogen [118,128]. When ACE is inhibited and Ang I is increased, conversion of Ang I to the bioactive peptide Ang-(1–7) by enzymatic reactions distinct from ACE may become more significant [129,130]. In addition, a decreased metabolism of Ang-(1–7) appears to contribute to the increase in Ang-(1–7) levels during ACE-inhibition because ACE degrades Ang-(1–7) to the inactive fragment Ang-(1–5) [131]. Ang-(1–7), has been shown to activate the AT2-receptor and/or putative non AT1/AT2 angiotensin receptor(s) [132,133], and accumulating evidence suggests that Ang-(1–7) may oppose the vasoconstrictor and growth-promoting actions of Ang II either directly or by stimulation of kinin, prostaglandin and nitric oxide release (reviewed in Ref. [134]). The possibility that increased Ang-(1–7) levels and AT2-receptor activation contribute to the antihypertrophic effects of ACE inhibitors warrants further investigation.

In the rat infarct model, AT1-receptor antagonists are equally effective as compared to ACE inhibitors in reducing cardiomyocyte hypertrophy and long-term mortality [135,136]. Recent studies indicate that the inhibition of cardiomyocyte hypertrophy by AT1-receptor blockade can not be attributed solely to an inhibition of Ang II–AT1-receptor signaling [125,126]. In fact, cotreatment with an AT2-receptor antagonist abolishes the attenuation of cardiomyocyte hypertrophy by AT1-receptor blockade in post MI rats, indicating that enhanced AT2-receptor stimulation significantly contributes to the antihypertrophic action of AT1-receptor blockade in this model [126]. In the same study, the blood pressure lowering effect of AT1-receptor blockade was not blunted by the AT2-receptor antagonist, indicating that afterload reduction per se does not mediate the antihypertrophic effects of AT1-receptor blockade [126]. Like ACE inhibitors, AT1-receptor blockers reduce interstitial fibrosis and decrease left ventricular volumes in post MI rats; intriguingly, both of these effects can be blunted by B2-kinin receptor blockade, indicating that a potentiation of kinins, possibly mediated through an enhanced stimulation of the AT2-receptor, may contribute to some of the beneficial effects of AT1-receptor antagonists in this model [125,126].

The rat model of ascending aortic stenosis represents another well characterized animal model of cardiac hypertrophy and failure. Clipping of the ascending aorta is followed initially by a stage of compensated concentric left ventricular hypertrophy. With time, however, ventricular dilation and systolic dysfunction develop, and herald the transition to cardiac failure and premature death [137]. In the early stage of compensated hypertrophy, left ventricular ACE mRNA expression and activity are elevated and associated with an increased intracardiac generation of Ang II [18,26]. Chronic ACE inhibition reduces cardiomyocyte hypertrophy, preserves contractile function, prevents the transition to failure and prolongs survival in this animal model [137,138]. Importantly, the beneficial effects of ACE inhibition occur in the presence of a sustained elevation of left ventricular systolic pressure, i.e. in contrast to the rat infarct model, the antihypertrophic effects of ACE inhibitors are not accompanied by a significant unloading of the ventricle [137,138]. Cardiac tissue ACE activity, however, is significantly inhibited during ACE inhibition [138], suggesting that the effects of ACE inhibitors may result from a reduced generation of Ang II and/or a potentiation of kinins or Ang-(1–7) locally within the heart. In contrast to ACE inhibition, chronic AT1-receptor blockade does not reduce cardiomyocyte hypertrophy and long term mortality in rats with aortic stenosis [139]. These results suggest that: (1) the beneficial effects of ACE inhibitors in this animal model do not relate to a reduced formation of Ang II and reduced AT1-receptor activation, and that (2) AT1-receptor independent pathways can promote cardiac hypertrophy in vivo - at least when the AT1-receptor is blocked.


   5 Studies in genetically engineered mice
Top
 Abstract
 1 Introduction
 2 Ang II-producing pathways...
 3 Ang II and...
 4 ACE-inhibitors and AT1...
 5 Studies in genetically...
References
 
Genetically engineered mice carrying gain-of-function or loss-of-function mutations of specific components of the RAS offer the unique opportunity to address the functional significance of Ang II signaling in a defined genetic background. In fact, physiological and molecular analyses of RAS-transgenic mice have allowed scientists to address some of the most fundamental questions related to the RAS and its putative role in cardiovascular pathophysiology. The development of microsurgical techniques, and the adaptation of experimental models of cardiac hypertrophy and failure to the mouse have been critical in this regard (reviewed in Ref. [140]).

To elucidate whether Ang II can activate a growth response in cardiac myocytes in vivo, independent from its hemodynamic effects, Hein et al. [141] have generated mice overexpressing the AT1A-receptor under the control of the cardiac myocyte-specific {alpha}MHC gene promotor. AT1A-transgenic mice exhibit a massive enlargement of the atria due to hyperplasia of atrial myocytes, and die shortly after birth, possibly related to bradycardia and heart block. As the murine {alpha}MHC gene promotor becomes activated in the ventricles only after birth, the effects of AT1A-overexpression in ventricular myocytes could not be assessed in this mouse model. However, the hyperplasia of atrial myocytes in AT1A-transgenic mice strongly suggests that Ang II can directly stimulate a growth response in cardiac myocytes via the AT1A-receptor [141]. In a recent study, Masaki et al. [142] overexpressed the AT2-receptor in the hearts of transgenic mice under the control of the {alpha}MHC promotor. In contrast to the {alpha}MHC–AT1A-transgenic mice, {alpha}MHC–AT2-transgenic mice survive to adulthood. AT2-transgenic mice show a decreased sensitivity to the pressor effects of Ang II, which is mainly due to an AT2-mediated negative chronotropic effect. Intriguingly, AT1-receptor-dependent activation of MAPK is blunted in AT2-transgenic hearts, suggesting that the AT2-receptor can oppose AT1-mediated growth responses in cardiac myocytes in vivo [142]. Considering that the AT2 to AT1-receptor ratio is increased in the failing human heart, and that the anti-hypertrophic effects of AT1-receptor antagonists may, in part, depend on AT2-receptor activation, this observation potentially bears clinical significance. Therefore, it will be critical to examine whether cardiac hypertrophy (e.g. in response to pressure overload) is blunted in {alpha}MHC–AT2-receptor transgenic mice.

Several groups have generated mice with a targeted disruption of the AT1A or AT2-receptor genes to study the functional importance of the two major Ang II receptor types in the in vivo context [143–146]. AT1A or AT2-receptor targeted mice are born according to Mendelian expectations and do not show any apparent histomorphological abnormalities of the heart, kidney or vasculature, indicating that AT1A and AT2-receptor-dependent signaling pathways are not required for a normal development of the cardiovascular system [143,146]. AT1A-receptor deficient mice are hypotensive as compared to normal littermates, demonstrating that the AT1A-receptor is indispensible for the regulation of resting blood pressure [143,144]. By contrast, inactivation of the AT2-receptor promotes hypertension, at least in some strain of mice [146]. Moreover, AT2-deficient mice display an enhanced pressure response to exogenous Ang II, indicating that the AT2-receptor normally serves to limit the pressure response of the AT1-receptor to Ang II [145,146]. Finally, AT2-knockout mice show subtle behavioural disturbances, including an impaired drinking response to water deprivation [145], and an attenuated exploratory behaviour [146].

Harada and co-workers [147,148] employed the AT1A-receptor knockout mouse to analyse whether the AT1A-receptor is required for the development of pressure overload cardiac hypertrophy in vivo. Although expression of the AT1B-receptor was detectable at very low levels in wild type and AT1A-receptor deficient hearts, infusions of subpressor doses of Ang II increased cardiac protooncogene expression and heart weight in wild type but not in AT1A-receptor deficient mice, indicating that the AT1B-receptor has no significant role in the promotion of cardiac hypertrophy by exogenous Ang II [147,148]. In sharp contrast, acute pressure overload induced by transverse aortic banding induced protooncogene expression and MAPK activation in wild type as well as in AT1A-receptor targeted mice [148]. Moreover, chronic abdominal aortic banding induced cardiac hypertrophy in control mice as well as in AT1A-receptor deficient mice. Intriguingly, the hypertrophic phenotype in AT1A-receptor targeted mice was virtually indistinguishable from wild type mice, and was characterized by an induction of fetal genes, a downregulation of sarcoplasmic reticulum Ca2+-ATPase, and increases in myocyte cross-sectional area and left ventricular fibrosis [147]. As shown by these elegant studies, Ang II–AT1A-receptor-dependent signaling pathways are not essential for the development of pressure overload hypertrophy in vivo. However, these data do not rule out that Ang II and the AT1A-receptor play a critical role in the activation of a hypertrophic response in a physiological context. These studies rather suggest that AT1-dependent and AT1-independent pathways exist, and that AT1-independent pathways can fully substitute for AT1-dependent pathways in pressure overload hypertrophy [147,149].

Time for primary review 28 days.


   References
Top
 Abstract
 1 Introduction
 2 Ang II-producing pathways...
 3 Ang II and...
 4 ACE-inhibitors and AT1...
 5 Studies in genetically...
 References
 

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