Angiotensin Converting Enzyme 2/Ang‐(1–7)/Mas Axis Protects Brain from Ischemic Injury with a Tendency of Age‐dependence

Zheng, Jian; Li, Guang-Ze; Chen, Shuzhen; Wang, Jinju; Olson, James E.; Xia, Hong-Fei; Lazartigues, Eric; Zhu, Yulan; Chen, Yanfang

doi:10.1111/cns.12233

Cited by 53 publications

(56 citation statements)

References 40 publications

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“…Activation of Ang-(1-7)-Mas-R signaling attenuates the development of hypertension and the pathologic progress of atherosclerosis [17,36]. A recent study has shown that neural over-expression of ACE2 lowers neurological deficit scores and leads to smaller stroke volumes following middle carotid artery occlusion-induced stroke in mice [19], suggesting that ACE2 protects the brain from ischemic injury. Also, this study suggests that activation of ACE2/Ang-(1-7)-Mas-R pathways can exert a direct neuroprotective action by alleviating ischemia-induced cell swelling and cell death [19].…”

Section: Discussionmentioning

confidence: 99%

“…A recent study has shown that neural over-expression of ACE2 lowers neurological deficit scores and leads to smaller stroke volumes following middle carotid artery occlusion-induced stroke in mice [19], suggesting that ACE2 protects the brain from ischemic injury. Also, this study suggests that activation of ACE2/Ang-(1-7)-Mas-R pathways can exert a direct neuroprotective action by alleviating ischemia-induced cell swelling and cell death [19]. In addition, ICV infusion of Ang-(1-7) or an ACE2 activator reduces ischemic injury in rats that are caused by a reduction in cerebral blood flow [18,31].…”

Section: Discussionmentioning

confidence: 99%

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Effects of Diabetic Hyperglycemia on Central Ang-(1-7)-Mas-R-nNOS Pathways in Spontaneously Hypertensive Rats

Liu²,

Ren³

et al. 2016

Cell Physiol Biochem

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Background/Aims: Hypertension is a major cause of stroke, and diabetes can increase incidence of this disease. We determined the role played by central angiotensin-(1-7) [Ang-(1-7)] pathway in modulating spontaneously hypertension with diabetic hyperglycemia. Methods: Western Blot analysis and ELISA were used to determine the protein expression of Ang-(1-7) and its signal pathway Mas-R-nNOS in the cerebral cortex and hippocampus of spontaneously hypertensive rats (SHR) and control animals. In a subset of animals, diabetic hyperglycemia was induced by systemic injection of streptozotocin (STZ). We analyzed a relationship between the levels of central Ang-(1-7) and plasma brain natriuretic peptide (BNP) indicating a risk of ischemic stroke. We further examined the effects of Ang-(1-7) on arterial blood pressure. Results: Our findings demonstrated for the first time that administration of STZ 1) attenuates the levels of Ang-(1-7) in the cerebral cortex and hippocampus, which are closely linked to plasma BNP; and 2) leads to downregulation of central Ang-(1-7)-Mas-R-nNOS pathways. Notably, STZ has greater effects in SHR. Additionally, inhibition of oxidative stress can largely improve downregulation of Ang-(1-7) in diabetic SHR. Moreover, central stimulation of Ang-(1-7) pathway or a blockade of oxidative stress improves systolic blood pressure in diabetic SHR. Conclusions: The Ang-(1-7) signaling pathway is engaged in the adaptive mechanisms associated with diabetic hypertension, suggesting that enhancing Ang-(1-7)-Mas-R-nNOS system is likely to be beneficial in preventing against cardiovascular and cerebrovascular dysfunction and vulnerability related to spontaneously hypertension, particularly to diabetic hypertension.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Effects of Diabetic Hyperglycemia on Central Ang-(1-7)-Mas-R-nNOS Pathways in Spontaneously Hypertensive Rats

Liu²,

Ren³

et al. 2016

Cell Physiol Biochem

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“…These findings are especially relevant from a translational perspective, as systemic treatment infusions were not started until 2 h after stroke. Importantly, the protective effects of the Ang-(1-7)–Mas system in stroke are preserved and may even be enhanced in aged animals [31•]. …”

Section: The Angiotensin-(1-7)–mas Axis and Strokementioning

confidence: 99%

Neuroprotective Mechanisms of the ACE2–Angiotensin-(1-7)–Mas Axis in Stroke

et al. 2015

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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.

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“…7,8 Ang(1-7) counterregulates Ang II actions through activation of the Mas G-protein-coupled receptor, 9,10 and attenuates reactive oxygen species (ROS) partly through decrease in NADPH oxidase (Nox) expression, [11][12][13] which plays a key role in the hypertension-induced ROS generation. 14,15 Thus, ACE2/Ang(1-7)/Mas axis pathway plays a protective role in the cardiovascular system against RAS.…”

Section: Introductionmentioning

confidence: 99%

Olmesartan Inhibits Cardiac Hypertrophy in Mice Overexpressing Renin Independently of Blood Pressure

Tanno

Tomita

Narita

et al. 2016

Journal of Cardiovascular Pharmacology

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Enhanced renin-angiotensin activity causes hypertension and cardiac hypertrophy. The angiotensin (Ang)-converting enzyme (ACE)2/Ang(1-7)/Mas axis pathway functions against Ang II type 1 receptor (AT1R) signaling. We investigated whether olmesartan (Olm), an AT1R blocker, inhibits cardiac hypertrophy independently of blood pressure, and evaluated the potential mechanisms. The 3- to 4-month-old male mice overexpressing renin in the liver (Ren-Tg) were given Olm (5 mg/kg/d) and hydralazine (Hyd) (3.5 mg/kg/d) orally for 2 months. Systolic blood pressure was higher in the Ren-Tg mice than in wild-type littermates. Olm and Hyd treatments lowered systolic blood pressure to the same degree. However, cardiac hypertrophy, evaluated by echocardiography, heart weight, cross-sectional area of cardiomyocytes, and gene expression, was inhibited by only Olm treatment, but not by Hyd. Olm treatment reversed decreased gene expressions of ACE2 and Mas receptor of Ren-Tg mice and inhibited enhanced NADPH oxidase (Nox)4 expression and reactive oxygen species, whereas Hyd treatment had no influence on them. These findings indicate that Olm treatment inhibits cardiac hypertrophy independently of blood pressure, not only through its original AT1R blockade but partly through enhancement of ACE2/Ang(1-7)/Mas axis and suppression of Nox4 expression.

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Angiotensin Converting Enzyme 2/Ang‐(1–7)/Mas Axis Protects Brain from Ischemic Injury with a Tendency of Age‐dependence

Cited by 53 publications

References 40 publications

Effects of Diabetic Hyperglycemia on Central Ang-(1-7)-Mas-R-nNOS Pathways in Spontaneously Hypertensive Rats

Effects of Diabetic Hyperglycemia on Central Ang-(1-7)-Mas-R-nNOS Pathways in Spontaneously Hypertensive Rats

Neuroprotective Mechanisms of the ACE2–Angiotensin-(1-7)–Mas Axis in Stroke

Olmesartan Inhibits Cardiac Hypertrophy in Mice Overexpressing Renin Independently of Blood Pressure

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