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It is now clear that the RAS is far more complex than previously conceived.
Landmark studies were crucial to establish this new concept. At the end of the s, Schiavone and co-workers Schiavone et al. Subsequently, several studies showed that Ang- exerts relevant cardiovascular and renal effects Benter et al. First, two independent research groups reported simultaneously in the existence and characterization of an enzyme homologue to ACE, the ACE2, which was established later as the main Ang- -forming enzyme Donoghue et al.
Second, Santos and co-workers discovered that the G-protein coupled Mas is a functional receptor for Ang- Santos et al. Thus, Ang- is now considered a biologically active member of the RAS, which binds to Mas inducing many beneficial actions, such as vasodilation, inhibition of cell growth, anti-thrombosis and anti-arrhythmogenic effects le Tran and Forster, ; Santos et al.
This is a strategic finding that may be exploited for therapeutic purposes Hernandez Prada et al. This knowledge may help in paving the way for the development of novel treatments for chronic inflammatory and renal diseases. Indeed, Ang II activates several cell functions and molecular signalling pathways related to tissue injury, inflammation and fibrosis, including calcium mobilization, free radical generation, activation of protein kinases and nuclear transcription factors, recruitment of inflammatory cells, adhesion of monocytes and neutrophils to endothelial and mesangial cells, up-regulation of adhesion molecules and stimulation of expression, synthesis and release of cytokines and chemokines Ruiz-Ortega et al.
Most of these actions of Ang II are mediated by the AT1 receptor and it has been suggested that blockade of the AT1 may be useful for the treatment of inflammatory diseases, as reviewed elsewhere Ruiz-Ortega et al. Indeed, there is now much evidence demonstrating that Ang- modulates negatively leukocyte migration, cytokine expression and release, and fibrogenic pathways Grobe et al.
Also, the stage of the disease apparently influences the expression of ACE2. At the early phase of myocardial infarction, ACE2 activity in plasma and left ventricles is increased in rats while the plasma and left ventricular ACE2 activities and mRNA levels are lower than in controls at 8 weeks postinfarction Ocaranza et al.
Similar findings were observed regarding the cardiac expression of Mas, i.
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The actions of Ang- 1—7 in coronary vessels include biochemical and functional alterations leading to vasodilatation either directly in artery rings or indirectly through bradykinin BK potentiation or by opposing Ang II actions Santos et al. This heptapeptide induced a concentration-dependent dilator response in porcine coronary artery rings, which were markedly attenuated by nitric oxide NO inhibition Porsti et al.
However, Gorelik et al. Furthermore, Ang- 1—7 elicited an increase in the vasodilator effect of BK in isolated perfused rat hearts.
This effect was dependent on Mas and NO and prostaglandin release Almeida et al. Ang- 1—7 also evoked vasodilation in isolated perfused mouse hearts involving interaction of Mas with AT1- and AT2-related mechanisms Castro et al. Together, these data suggest that Ang- 1—7 is a vasorelaxant peptide in the coronary bed and that this effect involves coupling to Mas and release of NO and prostaglandins. Nevertheless, because Neves et al.
This effect was not accompanied by consistent changes in contraction force and heart rate. A similar finding was observed in isolated hamster hearts Kumagai et al. Thus, low concentrations of Ang- 1—7 should be tested to clarify this important issue. It has been demonstrated that Ang- 1—7 decreases the incidence and duration of ischemia—reperfusion arrhythmias in isolated perfused rat hearts Ferreira et al.
These effects were abolished by ouabain De Mello Also, the antiarrhythmogenic effect of Ang- 1—7 was blocked by the Ang- 1—7 antagonist A and by the cyclooxygenase COX inhibitor indomethacin Ferreira et al. This peptide also improved postischemic contractile function in isolated heart preparations by a mechanism involving Mas and the release of BK and prostaglandins Ferreira et al.
In keeping with this latter data, transgenic mice overexpressing ACE2 in the heart presented sudden death due to cardiac arrhythmias Donoghue et al. These observations suggest that only very high local concentrations of Ang- 1—7 exert deleterious effects in the heart possibly through activation of NADPH oxidase Oudot et al.
In fact, transgenic rats presenting a local increase of Ang- 1—7 of up to fold in the heart did not show any sign of arrhythmias Ferreira et al.
Ang- 1—7 produced a significant increase in cardiac output and stroke volume in Wistar rats, partially attenuated by A Sampaio et al. These effects were also observed in transgenic rats that express a fusion protein capable of releasing Ang- 1—7 into circulating blood, increasing plasma concentration of this peptide 2. According to Loot et al. The vascular endothelial dysfunction observed in aortic rings from rats with myocardial infarction was also reversed by chronic infusion of Ang- 1—7 Loot et al.
In addition, Ang- 1—7 immunoreactivity was significantly increased in the tissue surrounding the infarct area of rat hearts with myocardial infarction Averill et al.
ACE2, angiotensin-(1-7) and Mas receptor axis in inflammation and fibrosis
We have observed that AVE preserved cardiac function and attenuated the development of hypertrophy and fibrosis in hearts from rats chronically treated with isoproterenol Ferreira et al.
This nonpeptide Ang- 1—7 analog also significantly improved the cardiac function in hearts subjected to myocardial infarction and preserved the myocardium after ischemia Ferreira et al. Furthermore, long-term treatment with AVE prevented the end-organ damage in hearts from spontaneously hypertensive rats treated with l-NAME Benter et al.
Taking advantage of this formulation, Marques et al. One of the most important beneficial effects of Ang- 1—7 is its ability to regulate the expression of extracellular matrix proteins and cardiac remodeling. Treatment of these cells with Ang- 1—7 inhibited Ang II-induced increases in collagen synthesis.
Chronic administration of this peptide significantly attenuated left ventricular hypertrophy and fibrosis in pressure-overloaded rats Wang et al. Importantly, deletion of Mas produced impairment of cardiac function associated with a significant increase in collagen type I, III and fibronectin content in the heart Santos et al. Moreover, amplification of the actions of BK Gorelik et al. Endothelial cells are not only involved in the production but also in the metabolism of this heptapeptide Velez et al.
Accordingly, Ang- 1—7 elicits relaxation in several vascular beds see Santos et al. In line with these observations, activation of endogenous ACE2 provokes reductions in arterial blood pressure of normal and hypertensive rats Hernandez Prada et al.
However, contradictory effects of Ang- 1—7 have been reported in human vessels. While Sasaki et al. Because plasma levels of Ang- 1—7 are increased during treatment with ACE inhibitors or AT1 receptor blockers part of their effects might be dependent on Ang- 1—7 Ferrario Several mechanisms are involved in the Ang- 1—7 vasodilatory effect, depending on the vessel diameter, the vascular regional bed, and the species.
Ang- 1—7 potentiates BK in several vascular beds and species. This BK-potentiating effect of Ang- 1—7 may contribute for its cardiovascular effects in normotensive Paula et al.
In addition, vascular Ang- 1—7 actions could involve modulation of vascular effects of Ang II Roks et al. Mas is involved in most of the known vascular effects of Ang- 1—7 and is present in human endothelial cells Santos et al. A link between Mas and NO release was described by Pinheiro et al. According to these authors, Ang- 1—7 induced phosphorylation of the stimulatory site Ser and dephosphorylation of the inhibitory site Thr Sampaio et al.
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These in vitro observations are in keeping with the effects of Ang- 1—7 on endothelial function in vivo Faria-Silva et al. Interestingly, untreated patients with essential hypertension present decreased amounts of Ang- 1—7 in the urine when compared with healthy volunteers Ferrario et al.
By using mass spectrometry, Grobe et al.
They reported that Ang- 1—7 and Ang- 1—4 were predominantly formed in the renal cortex, while Ang III was mainly produced in the renal medulla. Indeed, in the kidney NEP plays a key role in the degradation of Ang- 1—7 to form its metabolite Ang- 1—4. In another recent study, which investigated the localization of the renal RAS components by immunohistochemistry, ACE2 was predominantly found along the proximal nephron Pohl et al.
Moreover, ACE2 was reported to be fold more active in the mouse renal cortex than in cardiac tissue Wysocki et al. Although most of the studies reported that ACE2 is predominantly expressed in the renal cortex, there are still some controversies regarding its localization since i semiquantitative RT-PCR analysis revealed that ACE2 mRNA is found in all nephron segments — including the medulla with the exception of the medullary thick ascending limb of Henle's loop mTAL ; and ii ACE2 protein was detected by western blot and immunohistochemistry in the outer medulla and inner medulla, besides the renal cortex Li et al.
Recently, Pohl et al. The authors observed that megalin-deficient mice had a higher immunofluorescence staining for ACE2 when compared with megalin-positive cell populations. By contrast, ACE staining was weaker in brush border membranes of megalin-deficient proximal tubular cells.
This result suggests that megalin itself or megalin-related pathways regulate the expression of both isoforms in proximal tubular cells.
Mas seems to have a broad localization in the kidney. Indeed, functional Mas is detected in proximal tubules, as well as in the afferent arterioles, collecting ducts and the thick ascending limb of Henle and its expression is upregulated in renal ischemia Ren et al. Interestingly, Liu et al. The Ang- 1—7 effects in the kidney are quite complex and controversial.
In this context, Ang- 1—7 seems to limit transcellular sodium flux by modulating the activity of transporters via phospholipase A2 activation in tubular epithelial cells Andreatta-van Leyen et al.
This inhibitory effect is reversed by the AT2 receptor antagonist PD in a dose-dependent manner in the inner cortex basolateral membrane from pig kidney. Simoes e Silva et al. In addition, A treatment in virgin female rats leads to increased urinary volume and decreased osmolality with no changes in water intake Joyner et al.
However, it is important to point out that other Ang receptors than Mas e.