The discovery of beneficial neuroprotective effects of the angiotensin converting enzyme 2–angiotensin-(1-7)–Mas axis [ACE2–Ang-(1-7)–Mas] in ischemic and hemorrhagic stroke has spurred interest in a more complete characterization of its mechanisms of action. Here, we summarize findings that describe the protective role of the ACE2–Ang-(1-7)–Mas axis in stroke, along with a focused discussion on the potential mechanisms of neuroprotective effects of Ang-(1-7) in stroke. The latter incorporates evidence describing the actions of Ang-(1-7) to counter the deleterious effects of angiotensin II (AngII) via its type 1 receptor, including anti-inflammatory, anti-oxidant, vasodilatory, and angiogenic effects, and the role of altered kinase–phosphatase signaling. Interactions of Mas with other receptors, including bradykinin receptors and AngII type 2 receptors are also considered. A more complete understanding of the mechanisms of action of Ang-(1-7) to elicit neuroprotection will serve as an essential step toward research into potential targeted therapeutics in the clinical setting.

Caloric restriction has consistently been shown to extend life span and ameliorate aging-related diseases. These effects may be due to diet-induced reactive oxygen species acting to up-regulate sirtuins and related protective pathways, which research suggests may be partially inhibited by dietary anti-oxidant supplementation. Because caloric restriction is not sustainable long term for most humans, we investigated an alternative dietary approach, intermittent fasting (IF), which is proposed to act on similar biological pathways. We hypothesized that a modified IF diet, where participants maintain overall energy balance by alternating between days of fasting (25% of normal caloric intake) and feasting (175% of normal), would increase expression of genes associated with aging and reduce oxidative stress and that these effects would be suppressed by anti-oxidant supplementation. To assess the tolerability of the diet and to explore effects on biological mechanisms related to aging and metabolism, we recruited a cohort of 24 healthy individuals in a double-crossover, double-blinded, randomized clinical trial. Study participants underwent two 3-week treatment periods-IF and IF with anti-oxidant (vitamins C and E) supplementation. We found strict adherence to study-provided diets and that participants found the diet tolerable, with no adverse clinical findings or weight change. We detected a marginal increase (2.7%) in SIRT3 expression due to the IF diet, but no change in expression of other genes or oxidative stress markers analyzed. We also found that IF decreased plasma insulin levels (1.01 μU/mL). Although our study suggests that the IF dieting paradigm is acceptable in healthy individuals, additional research is needed to further assess the potential benefits and risks.

The angiotensin converting enzyme 2/angiotensin-(1-7)/Mas axis represents a promising target for inducing stroke neuroprotection. Here, explored stroke-induced changes in expression and activity of endogenous angiotensin converting enzyme 2 and other system components in Sprague Dawley rats. To evaluate the clinical feasibility of treatments that target this axis and that may act in synergy with stroke-induced changes, we also tested the neuroprotective effects of diminazene aceturate, an angiotensin converting enzyme 2 activator, administered systemically post-stroke. Amongst rats that underwent experimental endothelin-1-induced ischemic stroke, angiotensin converting enzyme 2 activity in the cerebral cortex and striatum increased in the 24 hours after stroke. Serum angiotensin converting enzyme 2 activity was decreased within 4h post stroke, but rebounded to reach higher than baseline levels 3d post-stroke. Treatment following stroke with systemically-applied diminazene resulted in decreased infarct volume and improved neurological function without apparent increases in cerebral blood flow. Central infusion of A-779, a Mas receptor antagonist, resulted in larger infarct volumes in diminazene-treated rats, and central infusion of the angiotensin converting enzyme 2 inhibitor MLN-4760 alone worsened neurological function. The dynamic alterations of the protective angiotensin converting enzyme 2 pathway following stroke suggest that it may be a favorable therapeutic target. Indeed, significant neuroprotection resulted from post-stroke angiotensin converting enzyme 2 activation, likely via Mas signaling in a blood flow-independent manner. Our findings suggest that stroke therapeutics that target the angiotensin converting enzyme 2/angiotensin-(1-7)/Mas axis may interact cooperatively with endogenous stroke-induced changes, lending promise to their further study as neuroprotective agents.

The goal of the present review is to examine the evidence for beneficial actions of manipulation of the RAS (renin-angiotensin system) in stroke, with particular focus on Ang-(1-7) [angiotensin-(1-7)] and its receptor Mas. The RAS appears to be highly involved in the multifactorial pathophysiology of stroke. Blocking the effects of AngII (angiotensin II) at AT1R (AngII type 1 receptor), through the use of commonly prescribed ACE (angiotensin-converting enzyme) inhibitors or AT1R blockers, has been shown to have therapeutic effects in both ischaemic and haemorrhagic stroke. In contrast with the deleterious actions of over activation of AT1R by AngII, stimulation of AT2Rs (AngII type 2 receptors) in the brain has been demonstrated to elicit beneficial effects in stroke. Likewise, the ACE2/Ang-(1-7)/Mas axis of the RAS has been shown to have therapeutic effects in stroke when activated, countering the effects of the ACE/AngII/AT1R axis. Studies have demonstrated that activating this axis in the brain elicits beneficial cerebral effects in rat models of ischaemic stroke, and we have also demonstrated the cerebroprotective potential of this axis in haemorrhagic stroke using stroke-prone spontaneously hypertensive rats and collagenase-induced striatal haemorrhage. The mechanism of cerebroprotection elicited by ACE2/Ang-(1-7)/Mas activation includes anti-inflammatory effects within the brain parenchyma. The major hurdle to overcome in translating these results to humans is devising strategies to activate the ACE2/Ang-(1-7)/Mas cerebroprotective axis using post-stroke treatments that can be administered non-invasively.

2016-12-23T18:47:23