The expression of angiotensin-converting enzyme 2–angiotensin-(1–7)–Mas receptor axis are upregulated after acute cerebral ischemic stroke in rats

Lu, Jie; Jiang, Teng; Wu, Liang; Li, Gao; Wang, Yao; Zhou, Feng; Zhang, Shuguang

doi:10.1016/j.npep.2013.09.002

Cited by 59 publications

(48 citation statements)

References 44 publications

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“…Ang-(1-7) treatment also decreased the number of haemorrhages in the striatum, improved neurological status (reduced lethargy), decreased the number of microglia in the striatum and tended to increase neuron survival at the same site [57]. Recently, it has been shown that cerebral infarction resulted in a significant increase in Ang-(1-7) and Mas receptor levels, as well as ACE2 levels, in the cerebral cortex compared with sham-operated rats, reinforcing the concept that this axis plays a pivotal role in the regulation of acute neuron injury in ischaemic cerebrovascular diseases [58].…”

Section: Beyond the Brain Effects Of Ang-(1-7) On Blood Pressurementioning

confidence: 79%

Protective axis of the renin–angiotensin system in the brain

et al. 2014

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The RAS (renin-angiotensin system) is composed of two arms: the pressor arm containing AngII (angiotensin II)/ACE (angiotensin-converting enzyme)/AT1Rs (AngII type 1 receptors), and the depressor arm represented by Ang-(1-7) [angiotensin-(1-7)]/ACE2/Mas receptors. All of the components of the RAS are present in the brain. Within the brain, Ang-(1-7) contributes to the regulation of BP (blood pressure) by acting at regions that control cardiovascular function such that, when Ang-(1-7) is injected into the nucleus of the solitary tract, caudal ventrolateral medulla, paraventricular nucleus or anterior hypothalamic area, a reduction in BP occurs; however, when injected into the rostral ventrolateral medulla, Ang-(1-7) stimulates an increase in BP. In contrast with AngII, Ang-(1-7) improves baroreflex sensitivity and has an inhibitory neuromodulatory role in hypothalamic noradrenergic neurotransmission. Ang-(1-7) not only exerts effects related to BP regulation, but also acts as a cerebroprotective component of the RAS by reducing cerebral infarct size and neuronal apoptosis. In the present review, we provide an overview of effects elicited by Ang-(1-7) in the brain, which suggest a potential role for Ang-(1-7) in controlling the central development of hypertension.

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Section: Beyond the Brain Effects Of Ang-(1-7) On Blood Pressurementioning

confidence: 79%

Protective axis of the renin–angiotensin system in the brain

et al. 2014

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“…The recent demonstration of increases in levels of ACE2, Ang-(1-7), and Mas in the 48h after stroke in the ischemic cerebral cortex of rats was an important first look 14 . A second study of transient MCAO in rats that examined axis components in the rostral ventrolateral medulla (RVLM) showed slightly different findings in that region, with decreases in Ang-(1-7) and Mas at 1d following stroke 15 .…”

Section: Discussionmentioning

confidence: 99%

“…It has recently been reported that expression of this protective axis is altered following stroke in the rat cerebral cortex 14 and rostral ventrolateral medulla 15 , although it is unknown whether ACE2 activity levels are affected or whether this is accompanied by changes in the deleterious angiotensin converting enzyme/angiotensin II/angiotensin II type 1 receptor (ACE/Ang II/AT1R) axis. Our objective was to test whether components of the RAS, including the ACE2/Ang-(1-7)/Mas pathway, are altered in rats following stroke.…”

Section: Introductionmentioning

confidence: 99%

Activation of the Neuroprotective Angiotensin-Converting Enzyme 2 in Rat Ischemic Stroke

et al. 2015

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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.

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“…Moreover, the intracerebral hemorrhage itself might have an independent effects on the levels of RAS components. The Ang-(1-7)-Mas axis has been shown to undergo dynamic changes in ischemic stroke [31]. Levels of Ang II are increased after ischemic stroke in the ventral cortex [32].…”

Section: Discussionmentioning

confidence: 99%

Angiotensin-(1–7) counteracts the effects of Ang II on vascular smooth muscle cells, vascular remodeling and hemorrhagic stroke: Role of the NFкB inflammatory pathway

Bihl

Zhang

Zhao

et al. 2015

Vascular Pharmacology

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Angiotensin (Ang)-(1-7) is a potential vasoprotective peptide. In the present study, we investigated its counteractive effects to Ang II on vascular smooth muscle cells (VSMCs) and intracerebral hemorrhagic stroke (ICH) through inflammatory mechanism. In in vitro experiments, human brain VSMCs (HBVSMCs) were treated with vehicle, Ang II, Ang II + Ang-(1-7), Ang II + A-779 or Ang II + Ang-(1-7) + A-779 (Mas receptor antagonist). HBVSMC proliferation, migration and apoptosis were determined by methyl thiazolyltetrazolium, wounding healing assay and flow cytometry, respectively. In in vivo experiments,C57BL/6 mice were divided into vehicle, Ang II, Ang II + Ang-(1-7), Ang II + A-779 or Ang II + Ang-(1-7) + A-779 groups before they were subjected to collagenase-induced ICH or sham surgery. Hemorrhage volume and middle cerebral artery (MCA) remodeling were determined by histological analyses. Levels of NFκB, Inhibitor of κBα (IκBα), tumor necrosis factor-α (TNF-α), monocyte chemoattractant protein 1 (MCP-1) and interleukin (IL-8) were measured by western blot or ELISA. We found that 1) Ang II increased HBVSMC migration, proliferation and apoptosis, and increased the blood pressure (BP), neurological deficit score, MCA remodeling and hemorrhage volume in ICH mice. 2) Ang-(1-7) counteracted these effects of Ang II, which was independent of BP, with the down-regulation of NFκB, up-regulation of IκBα, and decreased levels of TNF-α, MCP-1 and IL-8. 3) The beneficial effects of Ang-(1-7) could be abolished by A-779. In conclusion, Ang-(1-7) counteracts the effects of Ang II on ICH via modulating NFκB inflammation pathway in HBVSMCs and cerebral microvessels.

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The expression of angiotensin-converting enzyme 2–angiotensin-(1–7)–Mas receptor axis are upregulated after acute cerebral ischemic stroke in rats

Cited by 59 publications

References 44 publications

Protective axis of the renin–angiotensin system in the brain

Protective axis of the renin–angiotensin system in the brain

Activation of the Neuroprotective Angiotensin-Converting Enzyme 2 in Rat Ischemic Stroke

Angiotensin-(1–7) counteracts the effects of Ang II on vascular smooth muscle cells, vascular remodeling and hemorrhagic stroke: Role of the NFкB inflammatory pathway

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