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Review Articles |
Departments of 1 Physiology and Biophysics2 Morphology3 Pediatrics, Federal University of Minas Gerais, Belo Horizonte, MG, 31.270-901, Brazil
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(Received 8 January 2008;
accepted after revision 26 February 2008; first published online 29 February 2008)
Corresponding author: R. A. S. Santos: Departamento de Fisiologia e Biofísica, Avenida Antônio Carlos, 6627 – ICB – UFMG, 31 270-901 – Belo Horizonte, MG, Brasil. Email: marrob{at}dedalus.lcc.ufmg.br
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Introduction |
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Angiotensin(1–7) has been regarded for a long time as an inactive product of the renin–angiotensin system (RAS; Greene et al. 1982). This concept started to change with the studies of Schiavone et al. (1988) demonstrating that Ang(1–7) was equipotent to Ang II for releasing vasopressin from neurohypophysial explants in vitro and of Campagnole-Santos et al. (1989) describing decreases in arterial blood pressure upon microinjection of very low doses (femtomoles) of Ang(1–7) into the nucleus tractus solitarii. Since then, a considerable amount of work has been done, contributing ultimately to the remarkable change of our understanding of the renin–angiotensin cascade and functions (see Santos et al. 2000, 2005; Ferreira & Santos, 2005; Chappell, 2007 for review). Figure 1 illustrates our current view of the RAS.
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The two ACEs: role in Ang(1–7) formation and catabolism
The key role of ACE within the RAS has been well established since the pioneering work of Skeggs et al. (1956). The key role of ACE in the catabolism of Ang(1–7) was clearly established only about 30 years later (Deddish et al. 1998). As shown in Fig. 1, by forming the potent vasoconstrictor Ang II and inactivating the vasodilator Ang(1–7), ACE plays a central role as a pressor enzyme. An action outside the RAS, the inactivation of bradykinin (Bk), further strengthens the role of ACE as prohypertensive.
The biological role and relevance of Ang(1–7) was disregarded by many investigators because of the lack of a more specific enzymatic pathway for its formation (Greene et al. 1982). Many enzymes can generate Ang(1–7) from both Ang I and Ang II, including prolyl-endopeptidase (Greene et al. 1982), neutral-endopeptidase (Yamamoto et al. 1992) and prolyl-carboxypeptidase (Welches et al. 1991; Fig. 1). However, the non-specificity of their enzymatic activities did not support a direct role of these enzymes inside the RAS. It is important to note, however, that they did destroy Ang II in parallel to their Ang(1–7)-generating activity, suggesting an antihypertensive function within this peptide system.
In 2000, two independent groups shed light on the role of Ang(1–7), although the primary focus of these seminal studies did not include Ang(1–7) (Tipnis et al. 2000; Donoghue et al. 2000). Both groups described the identification of a homologue of ACE, which they called ACE2 (Donoghue et al. 2000) and captopril-insensitive carboxypeptidase (Tipnis et al. 2000). The name ACE2 was adopted by the literature. In the original work of Donoghue et al. (2000), ACE2 was described as having as a primary activity the hydrolysis of Ang I, generating Ang(1–9), serving as an indirect pathway to generate Ang II. However, this interpretation was challenged by the demonstration that Ang II was the preferable substrate for ACE2 (Tipnis et al. 2000; Vickers et al. 2002). Indeed, the catalytic efficiency of ACE2 against Ang II is 400-fold higher than for Ang I. Some of the similarities and differences of the two ACEs of the RAS are depicted in Fig. 2. It is also functionally remarkable that ACE2, in addition to generating Ang(1–7), does not metabolize bradykinin. However, the pro-inflammatory kinin, Des-Arg9-Bk, is efficiently hydrolysed by ACE2 but not by ACE.
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The ACE2–Ang(1–7)–Mas axis and the heart
One of the major recent advances in our understanding of the pathophysiological role of the ACE2–Ang(1–7)–Mas axis is related to its cardiac effects. Angiotensin(1–7) is present in the viable myocardium, and its formation appears to depend on Ang II as a substrate (Zisman et al. 2003; Averill et al. 2003). The expression of this peptide is associated with cardiac remodelling, in that it is lost in the infarcted area and significantly increased in the border area (Averill et al. 2003).
The elevated expression of Ang(1–7) in the failing heart tissue paralleled the expression of its forming enzyme, ACE2 (Santos et al. 2005). Several observations and experimental evidence suggest a beneficial role for ACE2 in cardiovascular function. Elevated ACE2 expression at the initial stage of several pathologies, which declines with progression of the disease, might indicate a protective role for ACE2. Genetic manipulation of ACE2 expression, either by targeted disruption or overexpression, suggests the possible significance of this enzyme in cardiac function (Crackower et al. 2002; Diez-Freire et al. 2006; Gurley et al. 2006). Despite the controversy concerning the consequences of ACE2 deficiency on basal heart function (Crackower et al. 2002; Gurley et al. 2006), it is becoming clear that ACE2 has a cardioprotective role in heart dysfunction induced by Ang II infusion (Huentelman et al. 2005) or increased after-load (Diez-Freire et al. 2006).
While a chronic increase of Ang II can induce many deleterious effects on the heart, Ang(1–7) appears to exert a cardioprotective role. It is well established that AT1 receptor stimulation by Ang II produces cardiac remodelling through a complex mechanism resulting in reduction of cardiac performance and increased susceptibility to cardiac events (Lijnen & Petrov, 2003). In contrast, Ang(1–7) can reduce or prevent cardiac remodelling by decreasing hypertrophy and fibrosis. Grobe et al. (2007b) have shown that Ang(1–7) prevents the cardiac fibrosis induced by Ang II infusion or Deoxycorticosterone acetate (DOCA)-salt treatment. A similar result was obtained by Benter and co-workers using L-NAME treatment (Benter et al. 2006). These findings are in line with the cardioprotective effect of Ang(1–7) described previously in cardiac infarction in rats (Loot et al. 2002) and in rats expressing an Ang(1–7)-producing fusion protein (Santos et al. 2004). The recent observations that genetic deletion of Mas impairs heart function and produces a marked change in the extracellular matrix toward a profibrotic state (Santos et al. 2006) and that ACE2 overexpression in the heart is able to protect the heart against myocardial injuries induced by Ang II infusion (Huentelman et al. 2005) or damages elicited by high blood pressure in spontaneously hypertensive rats (Diez-Freire et al. 2006) further strengthen the putative cardioprotective role of ACE2–Ang(1–7)–Mas. In keeping with these data, Iwata et al. (2005) have reported that in cardiac fibroblasts Ang(1–7) attenuates the production of endothelin-1 and leukaemia inhibitory factor induced by Ang II. Moreover, Tallant et al. (2005) presented evidence for a Mas-mediated antihypertrophic effect of Ang(1–7) in rat cardiomyocytes, and Grobe et al. (2007a) showed a decreased production of collagen induced by acute hypoxic exposure in cultured fibroblasts infected with ACE2 lentivirus. Worth mentioning is the fact that, besides preventing Ang II-induced morphological changes in the heart, Ang(1–7) has been reported to decrease cardiac Ang II levels (Mendes et al. 2005), an observation that was recently confirmed using transgenic rats TGR(A1-7)3292 which present chronic increases in plasma Ang(1–7) levels (Nadu et al. 2006).
A potential therapeutic application of the findings concerning Ang(1–7) is suggested by the beneficial effects of the orally active non-peptide Mas agonist, AVE 0991 (Pinheiro et al. 2004) obtained in heart dysfunction induced by L-NAME (Benter et al. 2006), by isoproterenol treatment (Ferreira et al. 2007b) and in coronary artery ligation (Ferreira et al. 2007a) in rats.
Angiotensin(1–7) and blood vessels
Angiotensin(1–7) can be formed in the vascular wall from Ang I or Ang II (Santos et al. 2000). In the human, endothelium ACE-independent as well as ACE-dependent pathways appear to take part. Since ACE2 is present in endothelial cells, it is supposed that it plays a major role in the Ang(1–7) formation, at least in the coronary circulation (Zisman et al. 2003), although evidence to the contrary has been presented (Campbell et al. 2004).
In addition to being an important site for generation of Ang(1–7), the endothelium is a major target for its actions. It is well documented that Ang(1–7) vasodilatory activity is endothelium dependent (for review see Santos et al. 2000, 2005; Ferreira & Santos, 2005; Chappell, 2007). Upon binding to endothelial cells, Ang(1–7) can stimulate the production of NO, prostaglandins or endothelium-derived relaxing factor (EDRF; Ferreira & Santos, 2005). The relative contribution of each of these endothelium-derived factors for the vasorelaxation induced by the peptide varies with the species and vascular territory (Santos et al. 2005).
The endothelium-dependent relaxation induced by Ang(1–7) in mouse aortic rings is absent in vessels derived from Mas-deficient mice (Santos et al. 2003). A clear link between Mas and NO release was first described by Pinheiro et al. (2004). Either Ang(1–7) or the Ang(1–7) receptor agonist, AVE 0991, elicited an increase in NO release in Mas-transfected CHO cells. This effect was blocked by the Mas antagonist, A-779, but not by AT1 or AT2 antagonists (Pinheiro et al. 2004). A major contribution to our understanding of how Ang(1–7) induces the release of NO has been provided by Sampaio et al. (2007). According to their findings, Ang(1–7) induces the release of NO through co-ordinated phosphorylation/dephosphorylation of the stimulatory and inhibitory sites of endothelial nitric oxide synthase (eNOS) in CHO Mas-transfected and in human aortic endothelial cells. Angiotensin(1–7) elicited phosphorylation of stimulatory site Ser1777 and dephosphorylation of inhibitory site Thr485. These effects involved as an upstream mechanism the activation of the phosphatidylinositol 3-kinase–protein kinase B (PI3K–Akt) pathway (Sampaio et al. 2007). A similar signalling cascade appears to be activated by Ang(1–7) acting through Mas in the heart (Giani et al. 2007) or more specifically in cardiomyocytes (Guatimosim S & Santos RAS, unpublished observations). The Mas antagonist, A-779, blocked all the effects of Ang(1–7) on the eNOS stimulation in these cell types.
The mechanisms involved in the release of prostaglandin and EDRF from endothelial cells remain largely unknown. It has been reported, however, that Ang(1–7) treatment elicited arachidonic acid release from CHO and COS cells transfected with Mas (Santos et al. 2003).
Based on the above findings, a therapeutic approach that would amplify or stimulate the ACE2–Ang(1–7)–Mas axis could provide protection against the development of cardiovascular diseases. It turns out that the merits of currently used drugs, the ACE inhibitors, AT1 receptor blockers and mineralocorticoid receptor blockers (Keidar et al. 2005), lay beyond their direct effects on suppression of the ACE–Ang II–AT1 receptor axis because they also increase cardiac ACE2 and/or Ang(1–7) significantly.
Angiotensin(1–7) and kidney function
Angiotensin(1–7) is present in the kidney in concentrations comparable to Ang II and produces complex renal effects (Santos et al. 2005). In water-loaded rats and mice, Ang(1–7) produces antidiuresis, probably through a mechanism involving cross-talk of Mas with AT1, AT2 and arginine vasopressin V2 receptors (Pinheiro et al. 2004; Santos et al. 2005). In contrast, in euvolaemic, anaesthetized animals Ang(1–7) is reported to produce natriuresis (Santos et al. 2005), an action which is in keeping with its in vitro effects on proximal tubular cells (Lara et al. 2006). However, data obtained with acute or chronic blockade of Ang(1–7) in non-anaesthetized rats (Santos et al. 2000) and more recently in TGR(A1–7)3292 rats (Ferreira et al. 2006) do not support a role for Ang(1–7) in promoting natriuresis. Therefore, additional studies are required in order to clarify the effects of Ang(1–7) in water and salt excretion.
Angiotensin-converting enzyme 2 is present in several nephron segments (Ye et al. 2006), where it is thought to be the main Ang(1–7)-forming enzyme (Chappel & Ferrario, 2006). Tubular ACE2 was decreased after 24 weeks of streptozotocin-induced diabetes in Sprague–Dawley rats (Tikellis et al. 2003) and in the glomeruli of diabetic db/db mice (Ye et al. 2006), while an increase was observed in renal cortex (Wysocki et al. 2006). Chronic blockade of ACE2 with its inhibitor, MLN-4760, in db/db mice (Ye et al. 2006) or in streptozotocin-induced diabetic mice (Soler et al. 2007) produced albuminuria, suggesting a protective role for ACE2 in the kidney. In this regard, Oudit et al. (2006) recently reported early accumulation of fibrillar collagen in the glomerular mesangium of male ACE2 mutant (ACE2–/y) mice, followed by development of glomerulosclerosis by 12 months of age, whereas female ACE2 mutant (ACE2–/–) mice were relatively protected. Progressive kidney injury was associated with increased deposition of collagen type I and III and fibronectin in the glomeruli and increased urinary albumin excretion compared with age-matched control mice. These structural and functional changes were prevented by treatment with the Ang II type 1 receptor antagonist, irbesartan. Loss of ACE2 was associated with a marked increase in renal lipid peroxidation product and formation and activation of mitogen-activated protein kinase and extracellular signal-regulated kinases 1 and 2 in glomeruli, events that were also prevented by irbesartan. The authors conclude that deletion of the ACE2 gene leads to the development of Ang II-dependent glomerular injury in male mice, suggesting that ACE2 might be an important therapeutic target in kidney (Oudit et al. 2006). It is not clear yet, however, whether this effect results from degradation of Ang II, formation of Ang(1–7), or both.
The recent observation that Mas mRNA is present in proximal tubular cells, where Ang(1–7) inhibits Ang II-induced phosphorylation of mitogen-activated protein (MAP) kinases, supports a putative renal protective role for Ang(1–7) (Su et al. 2006). The intriguing observation that pediatric patients with end-stage renal disease present a dramatic increase (25-fold) in plasma Ang(1–7) levels (Simões e Silva et al. 2006) further indicates that the ACE2–Ang(1–7)–Mas axis may have an hitherto unsuspected relationship with kidney function.
Other peripheral actions of ACE2–Ang(1–7)–Mas
Our group recently showed that the progression of liver dysfunction in bile-duct-ligated (BDL) rats is characterized by marked changes in Ang(1–7) levels and that the overall activation of the circulating RAS was associated in time with the progression of hepatic fibrosis (Pereira et al. 2007). Furthermore, the pharmacological blockade of the Ang(1–7) receptor, Mas, accelerated liver fibrosis by an increase in the liver content of collagen and transforming growth factor-β1 (Pereira et al. 2007). In line with these findings, Paizis et al. (2005) observed an upregulation of ACE2 and its widespread expression throughout the liver in BDL animals and in human cirrhosis. More recently, the same group showed that as BDL rats developed advanced fibrosis, increased expression of components of the classic RAS, such as ACE, AT1 receptor and Ang II, was accompanied by increased hepatic and plasma ACE2 activity, increased Mas expression in the liver and a major rise in plasma levels of Ang(1–7) (Herath et al. 2007). Indeed, recent studies (Paizis et al. 2005; Pereira et al. 2007; Herath et al. 2007) raise the possibility that upregulation of hepatic ACE2 and Mas and the generation of Ang(1–7) represent a counter-regulatory response to RAS-mediated liver injury.
There is substantial evidence to suggest that Ang(1–7) is involved in the beneficial actions of AT1 receptor blockers, ACE and vasopeptidase inhibitors (Ferrario et al. 2002). The studies with BDL rats also provide evidence that RAS blocking agents may attenuate liver fibrosis not only by antagonizing Ang II, but also by elevating Ang(1–7) levels. Thus, the administration of Ang(1–7) could be a useful tool to facilitate understanding of the mechanisms of fibrosis and should be further investigated for the treatment of liver diseases associated with fibrosis.
It has been described that Ang II and Ang(1–7) exhibit opposite effects on the regulation of cell growth. In a recent report, Gallagher & Tallant (2004) demonstrated that Ang(1–7) inhibited the growth of lung cancer cells by a mechanism presumably involving its receptor Mas and through inhibition of the extracellular signal-regulated kinase 1/2 (ERK1/2) signal transduction pathway. Angiotensin(1–7) also inhibited [3H]thymidine incorporation in vascular smooth muscle cells (VSMC) in response to stimulation by fetal bovine serum, platelet-derived growth factor and Ang II (Freeman et al. 1996). In addition, using a murine sponge model of angiogenesis, an antiproliferative effect of Ang(1–7) on fibrovascular tissue has been reported (Machado et al. 2000). The receptor Mas appears also to be involved in the antiproliferative effect of Ang(1–7) in VSMC and in stent-induced neointima proliferation (Langeveld et al. 2005). Furthermore, it has been demonstrated that Ang(1–7) inhibits vascular growth through prostaglandin-mediated intracellular events, inducing production of cAMP and reduction of Ang II-stimulated ERK1/2 activities (Tallant & Clark, 2003).
Polymorphism of ACE2
Since the discovery of ACE2 in 2000 (Tipnis et al. 2000; Donoghue et al. 2000), its functional relevance in mammals has become unequivocal. At the moment, it is clear that this carboxypeptidase is present in the cardiovascular system, as well as in organs involved in the control of blood pressure, such as brain and kidneys (Harmer et al. 2002). In addition, as mentioned above, this enzyme has provided more consistent support for the establishment of a counter-regulatory arm within the RAS, formed by ACE2 and its main catalytic product, Ang(1–7) (Crackower et al. 2002; Santos et al. 2005).
One interesting point raised in the last few years was the evidence that the genetic variability in the ACE2 gene might modulate the susceptibility to cardiovascular diseases (Frojdo et al. 2005; Lieb et al. 2006; Zhong et al. 2006; Yang et al. 2006). Following the first unsuccessful, tentative attempt to demonstrate that single nucleotides polymorphisms (SNPs) of ACE2 are involved in hypertension (Benjafield et al. 2004), many other studies have suggested that SNPs of this enzyme may be associated with increased left ventricular mass and septal wall thickness and ventricular hypertrophy (Lieb et al. 2006), coronary heart disease and myocardial infarction (Yang et al. 2006), and hypertension in patients with metabolic syndrome (Zhong et al. 2006). However, apparently ACE2 polymorphisms are not correlated with diabetic nephropathy (Frojdo et al. 2005). Possible associations between polymorphisms in RAS genes and susceptibility to cardiovascular pathologies are important topics for exploration in future studies, since these diseases result from the interaction of genes and various environmental factors, such as diet, physical activity and environmental stress. There are no reports about a possible correlation of SNPs of Mas with cardiovascular diseases.
Concluding remarks
The data briefly reviewed in this article support the two-arm RAS hypothesis. However, we are just starting to understand the complex relationship between the ACE–Ang II–AT1 receptor and ACE2–Ang(1–7)–Mas axis. The role of AT2 receptors, which in many instances oppose AT1-mediated responses (Carey, 2005), also needs to be considered. In this regard, it is interesting to note that AT2 expression decreases after birth, while, at least in testis, Mas expression is higher in adult animals (Alenina et al. 2002), suggesting that the AT2 counter-regulatory role in the early stages of life is progressively taken up by the ACE2–Ang(1–7)–Mas axis at later stages. Another important point, not addressed in this brief review, is related to the central actions of the two axes. In many instances, the actions evoked by Ang II and Ang(1–7) in the brain are similar, although the underlying mechanism appears to be different (Santos et al. 2000). Therefore, the central and peripheral RAS may be also different in terms of the two axes. Figure 4 summarizes the main Ang(1–7) actions.
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References |
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