Gender Influences Cerebral Vascular Responses to Angiotensin II Through Nox2-Derived Reactive Oxygen Species

Silva, T. Michael De; Broughton, Brad R.S.; Drummond, Grant Raymond; Sobey, Christopher G.; Miller, Alyson A.

doi:10.1161/strokeaha.108.531707

Cited by 73 publications

(64 citation statements)

References 20 publications

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“…Angiotensin II is known to increase superoxide production by cerebral vessels by activating the Nox-NADPH oxidases (Nox1-and Nox2-containing isoforms) and is commonly used to assess Nox activity in vessel preparations and vascular cells (16,27,28). Acylated ghrelin (0.1-10 nmol/l) had no significant effect on Nox activity, which is also consistent with our findings in intact mouse cerebral vessels (16) ( Figure 6C).…”

Section: Des-acylated Ghrelin Attenuates Superoxide Levels Nox Activsupporting

confidence: 89%

Protective actions of des-acylated ghrelin on brain injury and blood–brain barrier disruption after stroke in mice

Taher

Chin

et al. 2016

Clinical Science

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. (2016) Protective actions of des-acylated ghrelin on brain injury and blood-brain barrier disruption after stroke in mice. Clinical Science, 130(17), pp. 1545-1558. (doi:10.1042 This is the author's final accepted version.There may be differences between this version and the published version. You are advised to consult the publisher's version if you wish to cite from it.http://eprints.gla.ac.uk/135040/ AbstractThe major ghrelin forms, acylated ghrelin and des-acylated ghrelin, are novel gastrointestinal hormones. Moreover, emerging evidence indicates that these peptides may have other functions including neuro-and vaso-protection. Here, we investigated whether post-stroke treatment with acylated ghrelin or des-acylated ghrelin could improve functional and histological endpoints of stroke outcome in mice after transient middle cerebral artery occlusion. We found that des-acylated ghrelin (1 mg/kg) improved neurological and functional performance, reduced infarct and swelling, and decreased apoptosis. In addition, it reduced BBB disruption in vivo and attenuated the hyper-permeability of mouse cerebral microvascular endothelial cells after oxygen glucose deprivation and reoxygenation (OGD + RO). By contrast, acylated ghrelin (1 mg/kg or 5 mg/kg) had no significant effect on these endpoints of stroke outcome. Next we found that des-acylated ghrelin's vasoprotective actions were associated with increased expression of tight junction proteins (occludin and claudin-5), and decreased cell death. Moreover, it attenuated superoxide production, Nox activity, and expression of 3-nitrotyrosine. Collectively, these results demonstrate that poststroke treatment with des-acylated ghrelin, but not acylated ghrelin, protects against ischemia/reperfusion-induced brain injury and swelling, and BBB disruption by reducing oxidative and/or nitrosative damage. Summary statementStroke is a leading cause of death, but treatments are limited. This experimental study reveals that the hormone ghrelin powerfully protects the brain and its blood vessels against injury after stroke, raising the possibility that it could be exploited therapeutically. Short titleDes-acylated ghrelin protects against stroke. KeywordsIschemia, reperfusion, ghrelin, neuroprotection, blood-brain barrier. Abbreviations listBlood-brain barrier (BBB); ghrelin O-acyltransferase (GOAT); growth hormone secretagogue receptor 1a (GHSR1a); oxygen glucose deprivation and reoxygenation (OGD + Clinical perspectives• Ischemic stroke is a leading cause of mortality and long-term disability, but treatment options are limited. The major ghrelin forms, acylated ghrelin and des-acylated ghrelin, are novel gastrointestinal hormones. Moreover, recent evidence indicates these peptides may have neuroprotective and vasoprotective actions, and thus may protective actions in ischemic stroke.• In this study we tested whether the peptides could mediate protection in a clinically relevant mouse model of ischemic stroke.• Our findings reveal protective actions of des-acylated ghrelin whe...

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Section: Des-acylated Ghrelin Attenuates Superoxide Levels Nox Activsupporting

confidence: 89%

Protective actions of des-acylated ghrelin on brain injury and blood–brain barrier disruption after stroke in mice

Taher

Chin

et al. 2016

Clinical Science

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“…NADPH oxidase has been implicated as the primary source of increases in O 2 ·Ϫ production in the vasculature and kidneys of male experimental animals infused with ANG II (10,12,31,55), and increased NADPH oxidase activity has been reported in isolated vascular smooth muscle cells from male SHR treated with ANG II (6). Sex differences in NADPH oxidase have also been reported, with male C57BL/6 mice having greater cardiac NADPH oxidase enzymatic activity following ANG II infusion than females (13).…”

Section: Discussionmentioning

confidence: 99%

“…An acute dose of ANG II (0.1 mol/l) mediated greater superoxide (O 2 Ϫ ) and hydrogen peroxide (H 2 O 2 ) production in isolated cerebral arteries from male C57BL6/J mice than females (12), and chronic ANG II infusion increased plasma thiobarbituric acid reactive substances (TBARS), a marker of oxidative stress, in male, but not female, C57BL/6 mice (13). It is well established in male experimental animals that ANG II-mediated increases in oxidative stress contribute to the development of hypertension (28,59), and increased NADPH oxidase activity has been reported as a source of the excess O 2 Ϫ levels following ANG II infusion (27,29,21,13).…”

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confidence: 99%

Oxidative stress contributes to sex differences in angiotensin II-mediated hypertension in spontaneously hypertensive rats

Bhatia¹,

Elmarakby

El-Remessey³

et al. 2012

American Journal of Physiology-Regulatory, Integrative and Comp

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Bhatia K, Elmarakby AA, El-Remessey A, Sullivan JC. Oxidative stress contributes to sex differences in angiotensin II-mediated hypertension in spontaneously hypertensive rats. Am J Physiol Regul Integr Comp Physiol 302: R274 -R282, 2012. First published November 2, 2011; doi:10.1152/ajpregu.00546.2011.-NADPH oxidase has been implicated in ANG II-induced oxidative stress and hypertension in males; however, the contribution of oxidative stress to ANG II hypertension in females is unknown. In the present study, we tested the hypothesis that greater antioxidant capacity in female spontaneously hypertensive rats (SHR) blunts ANG II-induced oxidative stress and hypertension relative to males. Whole body and renal cortical oxidative stress levels were assessed in female and male SHR left untreated or following 2 wk of chronic ANG II infusion. Chronic ANG II infusion increased NADPH oxidase enzymatic activity in the renal cortex of both sexes; however, this increase only reached significance in female SHR. In contrast, male SHR demonstrated a greater increase in all measurements of reactive oxygen species production in response to chronic ANG II infusion. ANG II infusion increased plasma superoxide dismutase activity only in female SHR (76 Ϯ 9 vs. 190 Ϯ 7 Units·ml Ϫ1 ·mg Ϫ1 , P Ͻ 0.05); however, cortical antioxidant capacity was unchanged by ANG II in either sex. To assess the functional implication of alterations in NADPH enzymatic activity and oxidative stress levels following ANG II infusion, additional experiments assessed the ability of the in vivo antioxidant apocynin to modulate ANG II hypertension. Apocynin significantly blunted ANG II hypertension in male SHR (174 Ϯ 2 vs. 151 Ϯ 1 mmHg, P Ͻ 0.05), with no effect in females (160 Ϯ 11 vs. 163 Ϯ 10 mmHg). These data suggest that ANG II hypertension in male SHR is more dependent on increases in oxidative stress than in female SHR. superoxide; kidney; apocynin; NADPH oxidase THE RENIN-ANGIOTENSIN-ALDOSTERONE system (RAAS) is important in the regulation of body fluid and blood pressure homeostasis, and overactivation of the RAAS contributes to the development of numerous pathophysiological processes (20,21,40). There is an expanding literature regarding sex differences in the expression of RAAS components, as well as in functional responses to RAAS activation to both acute and chronic ANG II infusion (24,25,36,38,46). We recently published that greater levels of the vasodilatory peptide ANG (1-7) contribute to sex differences in the hypertensive response to chronic ANG II infusion in spontaneously hypertensive rats (SHR), although it is unknown whether there are additional molecular mechanism(s) contributing to sex differences in the blood pressure response to ANG II. Activation of angiotensin type 1 (AT 1 ) receptors mediate most well-known biological functions of ANG II, including the stimulation of oxidative stress, and female SHR have fewer AT 1 receptors than male SHR (43). However, little is known regarding the relative contribution of ANG II-mediated oxidative ...

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“…Basal ROS production in segments of mouse aorta was assessed by L012-enhanced chemiluminescence (11,12). The aortas were dissected out in their entirety as described in Assessment of Atherosclerotic Lesions, before being cut into 10 ring segments of 2 to 3 mm in length.…”

Section: Ros Detectionmentioning

confidence: 99%

Direct evidence of a role for Nox2 in superoxide production, reduced nitric oxide bioavailability, and early atherosclerotic plaque formation in ApoE^−/−mice

Judkins

Diep²,

Broughton

et al. 2010

American Journal of Physiology-Heart and Circulatory Physiology

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226

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The Nox family NADPH oxidases are reactive oxygen species (ROS)-generating enzymes that are strongly implicated in atherogenesis. However, no studies have examined which Nox isoform(s) are involved. Here we investigated the role of the Nox2-containing NADPH oxidase in atherogenesis in apolipoprotein E-null (ApoE−/−) mice. Wild-type (C57Bl6/J), ApoE−/−, and Nox2−/y/ApoE−/−mice were maintained on a high-fat (21%) diet from 5 wk of age until they were 12 or 19 wk old. Mice were euthanized and their aortas removed for measurement of Nox2 expression (Western blot analysis and immunohistochemistry), ROS production (L012-enhanced chemiluminescence), nitric oxide (NO) bioavailability (contractions to Nω-nitro-l-arginine), and atherosclerotic plaque development along the aorta and in the aortic sinus. Nox2 expression was upregulated in the aortic endothelium of ApoE−/−mice before the appearance of lesions, and this was associated with elevated ROS levels. Within developing plaques, macrophages were also a prominent source of Nox2. The absence of Nox2 in Nox2−/y/ApoE−/−double-knockout mice had minimal effects on plasma lipids or lesion development in the aortic sinus in animals up to 19 wk of age. However, an en face examination of the aorta from the arch to the iliac bifurcation revealed a 50% reduction in lesion area in Nox2−/y/ApoE−/−versus ApoE−/−mice, and this was associated with a marked decrease in aortic ROS production and an increased NO bioavailability. In conclusion, this is the first demonstration of a role for Nox2-NADPH oxidase in vascular ROS production, reduced NO bioavailability, and early lesion development in ApoE−/−mice, highlighting this Nox isoform as a potential target for future therapies for atherosclerosis.

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Gender Influences Cerebral Vascular Responses to Angiotensin II Through Nox2-Derived Reactive Oxygen Species

Cited by 73 publications

References 20 publications

Protective actions of des-acylated ghrelin on brain injury and blood–brain barrier disruption after stroke in mice

Protective actions of des-acylated ghrelin on brain injury and blood–brain barrier disruption after stroke in mice

Oxidative stress contributes to sex differences in angiotensin II-mediated hypertension in spontaneously hypertensive rats

Direct evidence of a role for Nox2 in superoxide production, reduced nitric oxide bioavailability, and early atherosclerotic plaque formation in ApoE^−/−mice

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Gender Influences Cerebral Vascular Responses to Angiotensin II Through Nox2-Derived Reactive Oxygen Species

Cited by 73 publications

References 20 publications

Protective actions of des-acylated ghrelin on brain injury and blood–brain barrier disruption after stroke in mice

Protective actions of des-acylated ghrelin on brain injury and blood–brain barrier disruption after stroke in mice

Oxidative stress contributes to sex differences in angiotensin II-mediated hypertension in spontaneously hypertensive rats

Direct evidence of a role for Nox2 in superoxide production, reduced nitric oxide bioavailability, and early atherosclerotic plaque formation in ApoE−/−mice

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Direct evidence of a role for Nox2 in superoxide production, reduced nitric oxide bioavailability, and early atherosclerotic plaque formation in ApoE^−/−mice