Angiotensin-(1–7): beyond its central effects on blood pressure

Abstract

Angiotensin (Ang) (1–7) is the main component of the depressor and protective arm of the renin-angiotensin system. Ang-(1–7) induces vasodilation, natriuresis and diuresis, cardioprotection, inhibits angiogenesis and cell growth and opposes the pressor, proliferative, profibrotic, and prothrombotic actions mediated by Ang II. Centrally, Ang-(1–7) induces changes in mean arterial pressure and this effect may be linked with its inhibitory neuromodulatory action on norepinephrine neurotransmission. The present review is focused on the role of Ang-(1–7) as a protective agent in the brain.

Keywords

angiogenesis angiotensin-(1–7)Mas receptor norepinephrine stroke

Introduction

The renin–angiotensin system (RAS) is composed of two arms. The pressor arm is represented mainly by angiotensin (Ang) II, the angiotensin-converting enzyme (ACE) and the Ang type 1 receptor (AT1R), while the depressor or protective arm is mainly represented by Ang-(1–7), Ang type 2 receptor (AT2R), the Mas receptor [through which Ang-(1–7) exerts its action] and ACE2. The Mas receptor, which was first described to be specific for Ang-(1–7) by Santos and colleagues in 2003 [Santos et al. 2003], belongs to the G protein-coupled receptor family, but is distinct from AT1R and AT2R. Several reports showed the lack of activation of conventional G protein signaling pathways upon stimulation with Ang-(1–7). For example, in Mas expressing cells the intracellular levels of the classical G protein-induced second messenger molecules such as calcium or inositol 1,4,5-trisphosphate were not altered upon Ang-(1–7) treatment [Tirupula et al. 2014]. Conversely, Mas activation leads to prostaglandin and nitric oxide (NO) generation as well as phosphoinositide 3 kinase (PI3K)/Akt and mitogen-activated protein kinase kinase (MEK) 1/2/extracellular-signal-regulated kinase (ERK) 1/2 pathways stimulation [Gironacci et al. 2014].

Ang-(1–7) is an endogenous counter-regulator of Ang II because it produces vasodilation, natriuresis and diuresis, and cardioprotection, inhibits angiogenesis and cell growth and opposes the pressor, proliferative, profibrotic and prothrombotic actions mediated by Ang II [Santos et al. 2013; Santos, 2014; Varagic et al. 2014].

All the components of the RAS are present in the brain [Karamyan and Speth, 2007]. Ang-(1–7) is formed from Ang I through cleavage at the Pro⁷–Phe⁸ peptide linkage by several endopeptidases, such as prolyl endopeptidase, thimet oligopeptidase or neutral endopeptidase (neprylisin) [Karamyan and Speth, 2007; Rice et al. 2004]. Alternatively, Ang-(1–7) is also formed from Ang II being processed by endopeptidases or carboxypeptidases which remove the carboxyl terminal phenylalanine, with ACE2 the primary enzyme (Figure 1) [Rice et al. 2004; Vickers et al. 2002]. The catalytic efficiency of ACE2 to generate Ang-(1–7) from Ang II is almost 500-fold greater than that shown for conversion of Ang I to Ang-(1–9) and 10- or 600-fold higher than that described for two other Ang-(1–7) forming enzymes, prolyl endopeptidase and prolyl carboxypeptidase, respectively [Vickers et al. 2002]. In fact, the protective effects of cerebral ACE2 on neurogenic hypertension and sympathetic activity are closely linked to the Ang-(1–7)/Mas receptor pathway [reviewed by Gironacci et al. 2014], showing the contribution of central ACE2 to Ang-(1–7) generation.

Figure 1.

Brain renin–angiotensin system.

Ang-(1–7) in stroke

Stroke is one of the leading causes of death and impaired quality of life as a result of neurological deficit. Stroke occurs when blood flow to the brain is interrupted, creating a central area of cell death (the core) surrounded by compromised tissue (the penumbra). Although the core of the damaged tissue is often beyond repair, the penumbra can recover function if blood flow is restored in a timely manner [Willis et al. 2011]. The pressor arm of the brain RAS is involved in ischemic brain damage after stroke. Numerous studies have demonstrated that AT1R blocker treatment can reduce infarct size and improve behavioral recovery in stroke models in normal rats, spontaneously hypertensive rats (SHR) and in atherosclerotic apolipoprotein E deficient mice [Willis et al. 2011]. Conversely, central administration of Ang-(1–7) reduces brain damage and improves neurological outcome in ischemic stroke [Mecca et al. 2011].

Intracerebroventricular (i.c.v.) infusion of Ang-(1–7) prior to and during ischemic stroke elicited by endothelin1-induced middle cerebral artery occlusion (MCAO) produced a significant reduction in the resulting intracerebral (cortical and striatal) infarct. This decrease in intracerebral infarct size was associated with increased neuron survival in the cortex and striatum, as well as decreases in the behavioral deficits caused by MCAO [Mecca et al. 2011]. A similar protective effect of Ang-(1–7) has been documented in a rat model of permanent MCAO [Jiang et al. 2012, 2014]. Supporting these findings is the fact that i.c.v. administration of the ACE2 activator, diminazene aceturate, under similar conditions as those used for Ang-(1–7) effectively decreased the intracerebral infarct and behavioral deficits resulting from endothelin-1-induced MCAO [Mecca et al. 2011]. These protective actions of Ang-(1–7) and diminazene aceturate were abolished by co-administration of the receptor Mas blocker, suggesting that is a Mas receptor mediated effect and supporting the involvement of Ang-(1–7) in the protective effects of the ACE2 activator [Mecca et al. 2011; Sumners et al. 2013]. In another model of stroke as in stroke-prone SHR, which is an established animal model of hypertension induced hemorrhagic stroke, central administration of Ang-(1–7) increases lifespan and improves the neurological status of these rats as well as reducing microglial numbers in the striatum, implying attenuation of cerebral inflammation [Regenhardt et al. 2014].

The beneficial actions of Ang-(1–7) in ischemic stroke are due to anti-inflammatory mechanisms. Thus, reductions in inducible nitric oxide synthase (NOS) gene expression, in the pro-inflammatory interleukin (IL) 1b and IL-6, and in microglial activation were elicited by Ang-(1–7) [Regenhardt et al. 2013; Sumners et al. 2013]. In addition, Ang-(1–7) decreased the levels of oxidative stress and suppressed nuclear factor-κB (NF-κB) activity, a transcriptional regulator involved in inflammation, which was accompanied by a reduction of pro-inflammatory cytokines and cyclooxynease-2 (COX-2) in the peri-infarct regions [Jiang et al. 2012]. Despite the fact that AT2Rs have been shown to be recognized by Ang-(1–7) [Bosnyak et al. 2011] and that a neuroprotective action has been reported for AT2Rs [Mogi and Horiuchi, 2013], the cerebroprotective effect of Ang-(1–7) was independent of AT2R activation. Ang-(1–7) beneficial effects on ischemic stroke were reversed by the Mas receptor antagonist but not by the AT2R antagonist, suggesting the involvement of the Mas receptor. Conversely, infusion of the Mas receptor antagonist alone increased oxidative stress levels and enhanced NF-κB activity, which was accompanied by an upregulation of pro-inflammatory cytokines and COX-2 [Jiang et al. 2012].

Neuronal overexpression of ACE2 protects the brain from ischemia-induced damage [Chen et al. 2014]. Overexpression of ACE2 in the neurons of human renin and angiotensinogen double transgenic mice, a model with central Ang II overproduction, displayed less MCAO-induced infarct volume and increased cerebral blood flow, neurological function and cerebral microvascular density in the peri-infarct area [Chen et al. 2014]. Blockade of the Mas receptor pathway in the brain partially abolished the beneficial effects of ACE2 overexpression. Furthermore, Ang (1-7)/Ang II ratio, angiogenic factors, endothelial NOS expression and NO production were increased, whereas NADPH oxidase subunits and reactive oxygen species were decreased in the brain of these transgenic mice [Chen et al. 2014]. These effects were independent of mean arterial pressure changes. Altogether, these results demonstrate that neuronal ACE2 protects brain from ischemic injury by changing the Ang-(1–7)/Ang II ratio [Chen et al. 2014]. The protective effect of neuronal ACE2 overexpression on ischemia was greater in older animals [Zheng et al. 2014b]. This was evidenced by lower neurological deficit scores and smaller stroke volumes in eight-month old transgenic mice compared with three-month ones [Zheng et al. 2014b]. In addition, brain tissue from these human renin and angiotensinogen transgenic mice with overproduction of ACE2 in neurons displayed less swelling and cell death in response to oxygen and glucose deprivation. This effect was blocked by the Mas receptor antagonist, suggesting that Ang-(1–7) production which results from ACE2 overexpression may exert this protective effect [Zheng et al. 2014a]. Thus, these data provide evidence that activation of ACE2/Ang-(1–7)/Mas pathway can exert a direct neuroprotective action by alleviating ischemia induced cell swelling and cell death [Zheng et al. 2014a].

Supporting the beneficial effects of the depressor arm of the RAS, it has been shown that the expression of the ACE2/Ang-(1–7)/Mas receptor axis is upregulated after acute cerebral ischemic stroke in rats [Lu et al. 2013]. Cerebral ischemic injury resulted in a significant increase of cerebral and circulating Ang-(1–7) at 6–48 hours following focal ischemic stroke compared with the control. Both Mas and ACE2 expression in the ischemic tissues and blood serum were markedly enhanced as a result of the acute ischemic insult. The Mas immunopositive neurons showed stronger expression in the ischemic cortex [Lu et al. 2013].

Ang-(1–7) and angiogenesis

Angiogenesis is a target for recovery after an ischemic stroke. Human studies have demonstrated that increased angiogenesis in the penumbra region is correlated with increased survival in stroke patients [Willis et al.2011]. The correlation between angiogenesis and improved functional outcome after ischemic stroke remains, and is seen in both animal models and in human stroke patients [Ergul et al. 2012]. The growth factors expressed may promote survival of the endothelial, glial and neuronal cell types in the penumbral area and the neovascularization may act to remove damaged tissue [Ergul et al. 2012]. Ang-(1–7) promotes brain angiogenesis. Infusion of Ang-(1–7) for 4 weeks promotes endothelial cell proliferation and increases brain capillary density in rats with permanent MCAO, which was accompanied by endothelial nitric oxide synthase (eNOS) activation and upregulation of nitric oxide (NO). Furthermore, Ang-(1–7)-induced brain angiogenesis attenuates the reduction of regional cerebral blood flow during subsequent ischemia and leads to the improvement in stroke outcome [Jiang et al. 2014]. Vascular endothelial growth factor (VEGF) is among the growth factors implicated in the recovery process after ischemic stroke [Ergul et al. 2012; Willis et al. 2011]. The level of VEGF, a main downstream effector of eNOS, was also increased in brain after Ang-(1–7) infusion. All these effects could be completely abolished by the Mas receptor blocker, implying that eNOS was a downstream effector of Ang-(1–7)/Mas signaling [Jiang et al. 2014].

Despite the fact that Ang-(1–7) and Mas receptor have been demonstrated to be involved in the generation of new blood vessels, little is known about their role in neuron generation. Mas expression was identified in dividing cells and in doublecortin-positive young neurons within the dentate gyrus of mice, one of the brain areas capable of adult neurogenesis [Freund et al. 2014]. Doublecortin is expressed by late mitotic active and early postmitotic young neurons, and may account for increased neurogenesis or maturation rate of this neuronal population. Lack of Mas, however, did not significantly affect cell proliferation and significantly increased the population of doublecortin-positive cells, indicating that Mas has a specific role for this neuronal population [Freund et al. 2014]. These results suggest that blockade of Mas might be beneficial in stimulating neurogenesis in adults.

Ang-(1–7) and cognitive function

Maintenance of brain function depends on a constant blood supply. Deficits in cerebral blood flow are linked to cognitive decline and they have detrimental effects on the outcome of ischemia [Pires et al. 2013]. Hypertension causes alterations in cerebral artery structure and function that can impair blood flow, particularly during an ischemic insult or during periods of low arterial pressure [Pires et al. 2013]. Chronic cerebral hypoperfusion is associated with cognitive decline in aging, vascular dementia and Alzheimer’s disease. Indeed, a role for the brain RAS in Alzheimer’s disease has been reported [Wright et al. 2013]. Ang-(1–7) was found to protect against cognitive dysfunction [Xie et al. 2014]. Ang-(1–7) significantly alleviated chronic cerebral hypoperfusion-induced cognitive deficits in rats subjected to permanent bilateral occlusion of the common carotid arteries, a model of chronic cerebral hypoperfusion. This neuroprotective effect was associated with increased NO generation, attenuated neuronal loss and suppressed astrocyte proliferation in the hippocampus [Xie et al. 2014]. Recently, it has been shown that Ang-(1–7) levels decreased in the brain of an animal model of Alzheimer’s disease during disease progression [Jiang et al. 2015]. In addition, an inverse correlation was found between Ang-(1–7) and tau hyperphosphorylation in brain, suggesting that Ang-(1–7) might be involved in the etiology and pathogenesis of Alzheimer’s disease, possibly via modulation of tau hyperphosphorylation [Jiang et al. 2015].

Ang-(1–7) protects the blood–brain barrier and neurons

Hypertension causes blood–brain barrier breakdown by mechanisms involving inflammation, oxidative stress and vasoactive circulating molecules. This exposes neurons to cytotoxic molecules, leading to neuronal loss, cognitive decline and impaired recovery from ischemia [Pires et al. 2013]. Recently, it has been shown that Ang-(1–7) exerts a protective role in blood–brain barrier damage. In cerebral ischemia reperfusion injury-induced and hypoxia-induced blood–brain barrier damage, Ang-(1–7) promotes the expression of zonula occludens-1 and claudin-5, which are proteins associated with tight junction in cerebral endothelial cells of the blood brain barrier [Wu et al. 2015].

In an attempt to elucidate the cellular target for the protective effect elicited by Ang-(1–7) in the brain, we investigated the different cellular type protected by Ang-(1–7) by transmission electron microscopy in the model of brain damage induced by Shiga toxin 2 (Stx2) producing enterohemorrhagic Escherichia coli. Stx2 induced neurodegeneration and axon demyelination. Ang-(1–7) prevented neuronal damage and hampered the Stx2-induced demyelination [Gironacci et al. 2013]. These effects were mediated by the Mas receptor (unpublished results).

Central Ang-(1–7) improves peripheral cardiovascular responses

Ang-(1–7) not only acts as a cerebroprotective when it is given in the brain. It is well known that Ang-(1–7) acting in different nucleus of the brain induces changes in arterial blood pressure (reviewed by Gironacci et al. 2013, 2014). For instance, a reduction in blood pressure occurred after i.c.v. Ang-(1–7) was observed in the nucleus of the nucleus tractus solitarii, caudal ventrolateral medulla, paraventricular nucleus or anterior hypothalamic area, while an increase in blood pressure was observed in the rostral ventrolateral medulla [Gironacci et al. 2013]. Recently, it has been shown that chronic increase in Ang-(1–7) levels in the brain improves both cardiovascular and metabolic parameters in an experimental model of metabolic syndrome [Guimaraes et al. 2014]. Chronic i.c.v. infusion of Ang-(1–7) attenuated the development of hypertension and improved the baroreflex control of heart rate and the glucose metabolism in fructose fed rats [Guimaraes et al. 2014].

Ang-(1–7) can act in the amygdala to attenuate the cardiovascular response to acute emotional stress. Injection of Ang-(1–7) into the basolateral amygdala blocked the tachycardia and the pressor response produced by air jet stress [Oscar et al. 2015]. These effects were completely reversed by the Mas receptor antagonist, indicating that Ang-(1–7) through the Mas receptors modulates the cardiovascular response evoked by emotional stress [Oscar et al. 2015]. Similar attenuating stress-induced tachycardia response were reported when Ang-(1–7) or the ACE2 activator compound, 1-[[2-(dimethylamino)ethyl]amino]-4-(hydroxymethyl)-7-[[(4-methylphenyl)sulfonyl]oxy]-9H-xanthen-9-one (XNT) were injected i.c.v. [Martins Lima et al. 2013]. XNT was able to evoke wide cardiovascular responses [Martins Lima et al. 2013]. XNT would achieve its effects not by forming only Ang-(1–7), but also by degrading Ang II. Thus, Ang-(1–7) can act in central circuits modulating anxiety and emotional stress responses.

Ang-(1–7) and norepinephrine

Ang-(1–7) central effects on blood pressure regulation and cardiovascular responses may be associated with changes in neurotransmitter synaptic levels. Sympathetic nervous activity in both central and peripheral nervous systems may play a major role in the regulation of blood pressure, and that hypertension is accompanied characteristically by increased sympathetic nervous activity in both humans and animal models [Tsuda, 2012]. The brain RAS may actively participate in the modulation of neurotransmitter release and influence the central sympathetic outflow to the periphery [Tsuda, 2012]. Ang II is well known to facilitate norepinephrine (NE) neurotransmission [Tsuda, 2012; Veersingham and Raizada, 2003]. In contrast to Ang II, Ang-(1–7) elicits a sympato-inhibitory action [Gironacci et al. 2013]. In neurons from the hypothalamus and brainstem of normotensive and SHR, Ang-(1–7) leads to a decrease in NE levels in the synaptic cleft. This effect results from a decrease in neurotransmitter release and synthesis and an increase in its neuronal uptake (Figure 2). Thus, Ang-(1–7) through Mas and AT2Rs elicits a reduction in NE release in hypothalami from normotensive and hypertensive rats in a bradykinin/NO-dependent manner through the cyclic guanosine monophosphate (cGMP)/protein kinase G (PKG) pathway which, in turn, maintains low NE outflow [Gironacci et al. 2000, 2004].

Figure 2.

Schematic representation of a sympathetic neuron and the targets of Ang-(1–7) action which results in norepinephrine (NE) levels changes in the synaptic cleft.

Ang-(1–7) not only induces a decrease in neurotransmitter release but also in its synthesis. The peptide, through an AT2R-mediated mechanism, downregulates tyrosine hydroxylase (TH), the rate-limiting enzyme in the biosynthesis of cathecolamines, reducing in consequence NE biosynthesis. Ang-(1–7) downregulates TH expression by increasing its degradation through stimulation of the ubiquitin–proteasome system, which is the major pathway for intracellular protein degradation in eukaryotic cells [Lopez Verrilli et al. 2009].

Synaptic neurotransmission requires the precise control of the duration and the magnitude of neurotransmitter action at specific molecular targets. Uptake of monoamine neurotransmitters into presynaptic terminals through the transporters is the main mechanism for monoaminergic neurotransmission ending. NE transporter (NET) regulates the clearance of NE from the synaptic cleft. Changes in the activity of NET should have a significant impact on the concentration and duration of NE present in the synaptic cleft, and thus NET is essential for a fine-tuned control of sympathetic activity [Bönisch and Brüss, 2006; Kvetnansky et al. 2009]. Ang-(1–7) does not evoke an acute effect on neuronal NE uptake. Conversely, Ang-(1–7) causes a long-term stimulatory effect on NE neuronal uptake by increasing NET transcription and expression. The Ang-(1–7)-stimulated NET expression is coupled to Mas receptor activation acting through a PI3-kinase/Akt and MEK 1/2-ERK1/2-dependent pathway [Lopez Verrilli et al. 2012].

Altogether, these results showed that Ang-(1–7) elicits a negative neuromodulatory role on NE neurotransmission, thus contributing to the modulation of NE homeostasis and maintaining appropriate synaptic NE levels during hypertensive conditions.

Conclusion

To date it is clear the role of Ang-(1–7) as a cerebroprotective agent. Therapies that induce an increase in centrally Ang-(1–7) levels may be considered possible approaches as neuroprotectives. For instance, ACE inhibitors lead to an increase in Ang-(1–7) levels [Ferrario et al. 2005] and they are widely used in stroke treatment. The ACE inhibitor captopril given subcutaneously has been shown to be neuroprotective in animal models of parkinsonism [Sonsalla et al. 2013]. Inhibition of ACE activity not only increases the generation of Ang-(1–7) from Ang I, but also reduces its degradation. Another possible therapy may be the systemic administration of an ACE2 activator, which favors Ang II degradation with the subsequent increase in Ang-(1–7) levels.

Footnotes

Funding

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Conflict of interest statement

The author declares no conflicts of interest in preparing this article.

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