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      The counter regulatory axis of the renin angiotensin system in the brain and ischaemic stroke: Insight from preclinical stroke studies and therapeutic potential

      review-article
      Author(s): a , a , a , b , *
      Publication date (Electronic):
      Journal: Cellular Signalling
      Publisher: The Author(s). Published by Elsevier Inc.
      Keywords: Renin angiotensin system, Ischaemic stroke, AT2R, Mas receptor, Ang-(1–7), Ang-(1–9), C21, AD, Alzheimer's disease, Aβ), amyloid β, Ang I), angiotensin I, Ang II), angiotensin II, Ang-(1–7)), angiotensin-(1–7), Ang-(1–9)), angiotensin-(1–9), ACE), angiotensin converting enzyme, ACE2), angiotensin converting enzyme 2, ACEi), angiotensin converting enzyme inhibitor, ARB), angiotensin receptor blocker, AT1R), angiotensin II type 1 receptor, AT2R), angiotensin II type 2 receptor, BBB), blood brain barrier, BP), blood pressure, B2R), bradykinin type 2 receptor, BDNF), brain derived neurotrophic factor, CBF), cerebral blood flow, C21), compound 21, DIZE), diminazene aceturate, eNOS), endothelial nitric oxide synthase, ET-1), endothelin-1, ERK 1/2), extracellular signal related kinase 1/2, GPCR), G-protein coupled receptor, MrgD), Mas related GPCR type D, MAPKs), mitogen activated protein kinases, NOX), NAD(P)H oxidases, nNOS), neuronal nitric oxide synthase, NO), nitric oxide, pMCAO), permanent middle cerebral artery occlusion, ROS), reactive oxygen species, RAS), renin angiotensin system, SHR), spontaneously hypertensive rat, tPA), tissue plasminogen activator, tMCAO), transient middle cerebral artery occlusion

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          Abstract

          Stroke is the 2nd leading cause of death worldwide and the leading cause of physical disability and cognitive issues. Although we have made progress in certain aspects of stroke treatment, the consequences remain substantial and new treatments are needed. Hypertension has long been recognised as a major risk factor for stroke, both haemorrhagic and ischaemic. The renin angiotensin system (RAS) plays a key role in blood pressure regulation and this, plus local expression and signalling of RAS in the brain, both support the potential for targeting this axis therapeutically in the setting of stroke. While historically, focus has been on suppressing classical RAS signalling through the angiotensin type 1 receptor (AT 1R), the identification of a counter-regulatory axis of the RAS signalling via the angiotensin type 2 receptor (AT 2R) and Mas receptor has renewed interest in targeting the RAS. This review describes RAS signalling in the brain and the potential of targeting the Mas receptor and AT 2R in preclinical models of ischaemic stroke. The animal and experimental models, and the route and timing of intervention, are considered from a translational perspective.

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          Global, regional, and national burden of stroke, 1990–2016: a systematic analysis for the Global Burden of Disease Study 2016

          Catherine Owens Johnson, Minh Tri Nguyen, Gregory A Roth … (2019)
          Summary Background Stroke is a leading cause of mortality and disability worldwide and the economic costs of treatment and post-stroke care are substantial. The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) provides a systematic, comparable method of quantifying health loss by disease, age, sex, year, and location to provide information to health systems and policy makers on more than 300 causes of disease and injury, including stroke. The results presented here are the estimates of burden due to overall stroke and ischaemic and haemorrhagic stroke from GBD 2016. Methods We report estimates and corresponding uncertainty intervals (UIs), from 1990 to 2016, for incidence, prevalence, deaths, years of life lost (YLLs), years lived with disability (YLDs), and disability-adjusted life-years (DALYs). DALYs were generated by summing YLLs and YLDs. Cause-specific mortality was estimated using an ensemble modelling process with vital registration and verbal autopsy data as inputs. Non-fatal estimates were generated using Bayesian meta-regression incorporating data from registries, scientific literature, administrative records, and surveys. The Socio-demographic Index (SDI), a summary indicator generated using educational attainment, lagged distributed income, and total fertility rate, was used to group countries into quintiles. Findings In 2016, there were 5·5 million (95% UI 5·3 to 5·7) deaths and 116·4 million (111·4 to 121·4) DALYs due to stroke. The global age-standardised mortality rate decreased by 36·2% (−39·3 to −33·6) from 1990 to 2016, with decreases in all SDI quintiles. Over the same period, the global age-standardised DALY rate declined by 34·2% (−37·2 to −31·5), also with decreases in all SDI quintiles. There were 13·7 million (12·7 to 14·7) new stroke cases in 2016. Global age-standardised incidence declined by 8·1% (−10·7 to −5·5) from 1990 to 2016 and decreased in all SDI quintiles except the middle SDI group. There were 80·1 million (74·1 to 86·3) prevalent cases of stroke globally in 2016; 41·1 million (38·0 to 44·3) in women and 39·0 million (36·1 to 42·1) in men. Interpretation Although age-standardised mortality rates have decreased sharply from 1990 to 2016, the decrease in age-standardised incidence has been less steep, indicating that the burden of stroke is likely to remain high. Planned updates to future GBD iterations include generating separate estimates for subarachnoid haemorrhage and intracerebral haemorrhage, generating estimates of transient ischaemic attack, and including atrial fibrillation as a risk factor. Funding Bill & Melinda Gates Foundation
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            Neuroprotection in acute stroke: targeting excitotoxicity, oxidative and nitrosative stress, and inflammation.

            Angel Chamorro, Ulrich Dirnagl, Xabier Urra … (2016)
            Treatments for acute ischaemic stroke continue to evolve after the superior value of endovascular thrombectomy was confirmed over systemic thrombolysis. Unfortunately, numerous neuroprotective drugs have failed to show benefit in the treatment of acute ischaemic stroke, making the search for new treatments imperative. Increased awareness of the relevance of rigorous preclinical testing, and appropriate selection of study participants, might overcome the barriers to progress in stroke research. Relevant areas of interest include the search for safe and effective treatment strategies that combine neuroprotection reperfusion, better use of advanced brain imaging for patient selection, and wider implementation of prehospital conducted clinical trials. Randomised controlled trials of combination treatments completed within the past 5 years have included growth factors, hypothermia, minocycline, natalizumab, fingolimod, and uric acid; the latter two drugs with alteplase produced encouraging results. Blocking of excitotoxicity is also being reassessed in clinical trials with new approaches, such as the postsynaptic density-95 inhibitor NA-1, or peritoneal dialysis to remove excess glutamate. The findings of these randomised trials are anticipated to improve treatment options and clinical outcomes in of patients with acute stroke.
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              Use of blood pressure lowering drugs in the prevention of cardiovascular disease: meta-analysis of 147 randomised trials in the context of expectations from prospective epidemiological studies

              M R Law, J K Morris, N Wald (2009)
              Objectives To determine the quantitative efficacy of different classes of blood pressure lowering drugs in preventing coronary heart disease (CHD) and stroke, and who should receive treatment. Design Meta-analysis. Data source Medline (1966-2007). Study selection Randomised trials of blood pressure lowering drugs recording CHD events and strokes. 108 trials studied differences in blood pressure between study drug and placebo (or control group not receiving the study drug) (“blood pressure difference trials”), and 46 trials compared drugs (“drug comparison trials”). Seven trials with three randomised groups fell into both categories. The results were interpreted in the context of those expected from the largest published meta-analysis of cohort studies, totalling 958 000 people. Participants 464 000 people defined into three mutually exclusive categories: participants with no history of vascular disease, a history of CHD, or a history of stroke. Results In the blood pressure difference trials β blockers had a special effect over and above that due to blood pressure reduction in preventing recurrent CHD events in people with a history of CHD: risk reduction 29% (95% confidence interval 22% to 34%) compared with 15% (11% to 19%) in trials of other drugs. The extra effect was limited to a few years after myocardial infarction, with a risk reduction of 31% compared with 13% in people with CHD with no recent infarct (P=0.04). In the other blood pressure difference trials (excluding CHD events in trials of β blockers in people with CHD), there was a 22% reduction in CHD events (17% to 27%) and a 41% (33% to 48%) reduction in stroke for a blood pressure reduction of 10 mm Hg systolic or 5 mm Hg diastolic, similar to the reductions of 25% (CHD) and 36% (stroke) expected for the same difference in blood pressure from the cohort study meta-analysis, indicating that the benefit is explained by blood pressure reduction itself. The five main classes of blood pressure lowering drugs (thiazides, β blockers, angiotensin converting enzyme inhibitors, angiotensin receptor blockers, and calcium channel blockers) were similarly effective (within a few percentage points) in preventing CHD events and strokes, with the exception that calcium channel blockers had a greater preventive effect on stroke (relative risk 0.92, 95% confidence interval 0.85 to 0.98). The percentage reductions in CHD events and stroke were similar in people with and without cardiovascular disease and regardless of blood pressure before treatment (down to 110 mm Hg systolic and 70 mm Hg diastolic). Combining our results with those from two other studies (the meta-analyses of blood pressure cohort studies and of trials determining the blood pressure lowering effects of drugs according to dose) showed that in people aged 60-69 with a diastolic blood pressure before treatment of 90 mm Hg, three drugs at half standard dose in combination reduced the risk of CHD by an estimated 46% and of stroke by 62%; one drug at standard dose had about half this effect. The present meta-analysis also showed that drugs other than calcium channel blockers (with the exception of non-cardioselective β blockers) reduced the incidence of heart failure by 24% (19% to 28%) and calcium channel blockers by 19% (6% to 31%). Conclusions With the exception of the extra protective effect of β blockers given shortly after a myocardial infarction and the minor additional effect of calcium channel blockers in preventing stroke, all the classes of blood pressure lowering drugs have a similar effect in reducing CHD events and stroke for a given reduction in blood pressure so excluding material pleiotropic effects. The proportional reduction in cardiovascular disease events was the same or similar regardless of pretreatment blood pressure and the presence or absence of existing cardiovascular disease. Guidelines on the use of blood pressure lowering drugs can be simplified so that drugs are offered to people with all levels of blood pressure. Our results indicate the importance of lowering blood pressure in everyone over a certain age, rather than measuring it in everyone and treating it in some.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Cell Signal
                Journal ID (iso-abbrev): Cell Signal
                Title: Cellular Signalling
                Publisher: The Author(s). Published by Elsevier Inc.
                ISSN (Print): 0898-6568
                ISSN (Electronic): 1873-3913
                Publication date PMC-release: 13 October 2020
                Publication date (Electronic): 13 October 2020
                Electronic Location Identifier: 109809
                Affiliations
                [a ]Institute of Cardiovascular & Medical Sciences, College of Medical, Veterinary & Life Sciences, University of Glasgow, Glasgow, UK
                [b ]BHF Glasgow Cardiovascular Research Centre, Institute of Cardiovascular & Medical Sciences, University of Glasgow, 126 University Place, Glasgow G12 8TA, UK
                Author notes
                [* ]Corresponding author.
                Article
                Publisher Item ID: S0898-6568(20)30286-2 Publisher ID: 109809
                DOI: 10.1016/j.cellsig.2020.109809
                PMC ID: 7550360
                SO-VID: dc3d6c33-af51-499e-a715-f3bdaae26a61
                Copyright © © 2020 The Author(s). Published by Elsevier Inc.
                License:

                Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active.

                History
                Date received : 13 July 2020
                Date revision received : 8 October 2020
                Date accepted : 9 October 2020
                Categories
                Subject: Review

                ScienceOpen disciplines: Cell biology
                Keywords: renin angiotensin system,ischaemic stroke,at2r,mas receptor,ang-(1–7),ang-(1–9),c21,ad, alzheimer's disease,aβ), amyloid β,ang i), angiotensin i,ang ii), angiotensin ii,ang-(1–7)), angiotensin-(1–7),ang-(1–9)), angiotensin-(1–9),ace), angiotensin converting enzyme,ace2), angiotensin converting enzyme 2,acei), angiotensin converting enzyme inhibitor,arb), angiotensin receptor blocker,at1r), angiotensin ii type 1 receptor,at2r), angiotensin ii type 2 receptor,bbb), blood brain barrier,bp), blood pressure,b2r), bradykinin type 2 receptor,bdnf), brain derived neurotrophic factor,cbf), cerebral blood flow,c21), compound 21,dize), diminazene aceturate,enos), endothelial nitric oxide synthase,et-1), endothelin-1,erk 1/2), extracellular signal related kinase 1/2,gpcr), g-protein coupled receptor,mrgd), mas related gpcr type d,mapks), mitogen activated protein kinases,nox), nad(p)h oxidases,nnos), neuronal nitric oxide synthase,no), nitric oxide,pmcao), permanent middle cerebral artery occlusion,ros), reactive oxygen species,ras), renin angiotensin system,shr), spontaneously hypertensive rat,tpa), tissue plasminogen activator,tmcao), transient middle cerebral artery occlusion
                Data availability:
                ScienceOpen disciplines: Cell biology
                Keywords: renin angiotensin system, ischaemic stroke, at2r, mas receptor, ang-(1–7), ang-(1–9), c21, ad, alzheimer's disease, aβ), amyloid β, ang i), angiotensin i, ang ii), angiotensin ii, ang-(1–7)), angiotensin-(1–7), ang-(1–9)), angiotensin-(1–9), ace), angiotensin converting enzyme, ace2), angiotensin converting enzyme 2, acei), angiotensin converting enzyme inhibitor, arb), angiotensin receptor blocker, at1r), angiotensin ii type 1 receptor, at2r), angiotensin ii type 2 receptor, bbb), blood brain barrier, bp), blood pressure, b2r), bradykinin type 2 receptor, bdnf), brain derived neurotrophic factor, cbf), cerebral blood flow, c21), compound 21, dize), diminazene aceturate, enos), endothelial nitric oxide synthase, et-1), endothelin-1, erk 1/2), extracellular signal related kinase 1/2, gpcr), g-protein coupled receptor, mrgd), mas related gpcr type d, mapks), mitogen activated protein kinases, nox), nad(p)h oxidases, nnos), neuronal nitric oxide synthase, no), nitric oxide, pmcao), permanent middle cerebral artery occlusion, ros), reactive oxygen species, ras), renin angiotensin system, shr), spontaneously hypertensive rat, tpa), tissue plasminogen activator, tmcao), transient middle cerebral artery occlusion

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