The angiotensin-converting enzyme 2-angiotensin-(1-7) axis: the other side of the renin-angiotensin system
Year: 2011
Type: article
Abstract: The renin–angiotensin system (RAS) is a peptide hormone system that plays an important role in cardiovascular physiology by regulating vascular, kidney and heart function. Classically, the RAS pathway was considered to be an endocrine system with circulating angiotensin II (Ang II) as its functional effector hormone, produced by the action of angiotensin-converting enzyme 1 (ACE1) on angiotensin I. More recently, however, with the advent of new molecular techniques, there have been significant changes in our understanding of this system. A new axis has emerged, the angiotensin-converting enzyme 2 (ACE2)–Ang-(1–7)–Mas receptor axis. Angiotensin-converting enzyme 2 is a new member of the ACE family, which predominantly metabolizes Ang II to generate Ang-(1–7). Angiotensin-(1–7) possesses opposing properties to Ang II. By acting through the Mas receptor, Ang-(1–7) promotes vasodilatation and inhibits proliferation and hypertrophy (Santos et al. 2003; Ferrario et al. 2005). Growing evidence now indicates that by cleaving Ang II into Ang-(1–7), ACE2 plays a pivotal role in counterbalancing the deleterious actions of the ACE–Ang II–Ang II type 1 (AT1) receptor axis. Thus, activation of the ACE2 axis may be beneficial in pathological conditions where the RAS is critically involved, especially in many cardiovascular or neurovascular diseases. In this issue of Experimental Physiology, Mecca et al. (2011) report that Ang-(1–7) exerts a potent protective effect against cerebral ischaemic stroke induced by intracerebral administration of endothelin-1 (ET-1) in rats. This report contributes to the ongoing efforts to understand the full potential of the ACE2–Ang-(1–7)–Mas axis. Angiotensin-(1–7) has been detected in neuronal cell bodies and fibre tracts of magnocellular nuclei in brain areas including the hypothalamus, medulla oblongata and amygdala, as well as in the cerebral cortex of normal rats. In addition, the Ang-(1–7) receptor Mas was also detected in neurons, microglia and endothelial cells in brain, suggesting a possible involvement of this axis in normal brain function (Shi et al. 2010; Xu et al. 2011). More importantly, ACE2 has been shown to be widely expressed throughout the brain. It was detected not only in the cardiorespiratory neurons of the brainstem but also in non-cardiovascular areas, such as the motor cortex and raphe (Doobay et al. 2007). Such a pattern of expression of the ACE2–Ang-(1–7)–Mas axis suggests a broad effect of this axis in the central nervous system, in addition to its ability to regulate cardiovascular function. These studies not only change our classical view of RAS but also improve our understanding of various neurovascular diseases, including stroke. The study by Mecca et al. (2011) is the first report to demonstrate a potent beneficial effect of the Ang-(1–7) axis in cerebral stroke. They report that intracerebroventricular infusion of either Ang-(1–7) or an ACE2 activator, diminazine aceturate (DIZE), prior to and following ET-1-induced middle cerebral artery occlusion, significantly attenuates the cerebral infarct size and neurological deficits measured 72 h after the insult. These beneficial actions appear to be mediated by the Mas receptor, because intracerebroventricular co-administration of the Mas receptor inhibitor A-779 prevents these effects. Administration of Ang-(1–7) for 7 days does not alter either the acute middle cerebral artery constriction and the reduction in cerebral blood flow induced by ET-1 or the systemic blood pressure, implicating a non-haemodynamic protective effect of Ang-(1–7). In contrast, the intracerebroventricular administration of DIZE for 7 days significantly reduces the systemic blood pressure. There might be two possibilities responsible for such a discrepancy. The first possibility is that the ACE2 activation by DIZE at the concentration used in the present study produces a much higher level of Ang-(1–7) than the concentration of Ang-(1–7) infused. The second possibility is that DIZE also elicits a non-ACE2 mechanism which is involved in blood pressure regulation. Measurment of Ang-(1–7) levels in different brain regions after stroke or DIZE administration would probably provide us with a clear picture. Interestingly, Mas antagonism with A-779 alone does not appear to worsen the ET-1-induced cerebral damage and behavioural deficit, suggesting that endogenous Ang-(1–7) probably does not play a significant protective role in the present stroke model. However, stimulation of Mas receptors with endogenous Ang-(1–7) by activating ACE2 using DIZE evidently reveals a potent cerebroprotective action of this axis. The lack of any detectable systemic haemodynamic effect with intracerebroventricular administration of Ang-(1–7) or A-779 in the present study indicates that these drugs probably do not reach the brain areas known to be involved in blood pressure regulation. Likewise, a recent study demonstrated that brain-selective overexpression of human ACE2 was unable to alter the baseline haemodynamic parameters in mice (Feng et al. 2010). The overexpression of neuronal ACE2, however, did attenuate the development of Ang II-induced neurogenic hypertension, possibly by enhancing nitric oxide release in the brain as a result of upregulation of Mas and Ang II type 2 receptors. Angiotensin-(1–7) also possesses vasodilator properties and has been shown to increase blood flow and vascular conductance in the kidney, mesentery, skin and brain after intravenous administration at a dose of 110 fmol min-1 for 10 min (Sampaio et al. 2003). Such an action of Ang-(1–7) could contribute to its cerebroprotective effect by increasing blood supply to the ischaemic region. In the study by Mecca et al. (2011), no change in cerebral blood flow in the ischaemic core and penumbra is observed after Ang-(1–7) treatment for 7 days. However, cerebral blood flow is monitored only during 60 min of ET-1-induced middle cerebral artery occlusion and may not necessarily represent the overall haemodynamic effect of Ang-(1–7) treatment for 7 days. Therefore, the possibility of involvement of a haemodynamic-dependent effect in the observed cerebroprotective action of Ang-(1–7) cannot be completely ruled out. Nevertheless, the study by Mecca et al. (2011) highlights a potent protective role of the central ACE2–Ang-(1–7) axis and its potential benefits as a therapeutic target in cerebrovascular diseases such as stroke and neurological deficits. Mecca et al. (2011) suggest a role for inducible nitric oxide synthase (iNOS) and nitric oxide in the cerebroprotective action of Ang-(1–7), by measuring reduced iNOS mRNA expression in the brain 3 days after ischaemic injury. These results are complementary to the reduction in infarct size by Ang-(1–7) or DIZE. However, iNOS is considered a secondary or late marker in ischaemic injury and therefore might not represent the immediate underlying target triggered by Ang-(1–7). Previously, various early protective mechanisms have been attributed to Ang-(1–7), such as phosphorylation and activation of endothelial NOS, an early increase in the nitric oxide level, an increase in the ratios of AT2/AT1 receptors and Mas/AT1 receptor expression (Feng et al. 2010). Whether these actions (especially in the intracerebral ischaemic zone) contribute to the observed cerebroprotective effect of the ACE2–Ang-(1–7) axis during stroke remains to be determined. Furthermore, a large body of evidence points towards an important role for oxidative stress in the induction of pro-inflammatory genes and neuro-inflammation following stroke by activating the redox-sensitive transcription factor nuclear factor-κB. Future investigations are warranted to determine whether Ang-(1–7) modulates the oxidative stress-induced inflammatory mechanism, thereby mediating its cerebroprotective effect during stroke. Elucidation of the detailed and precise mechanistic profile of the ACE2–Ang-(1–7) axis will provide us with a better understanding of this physiologically neuroprotective pathway of the RAS. It will also open new avenues for the discovery of novel and effective diagnostic and therapeutic targets for the treatment of cerebral stroke and associated neurological deficits.
Source: Experimental Physiology
Author: Mohd Shahid
Language: English
Subfield: Cardiology and Cardiovascular Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W2147447951