Hypertonic Mannitol Loading of NF-κB Transcription Factor Decoys in Human Brain Microvascular Endothelial Cells Blocks Upregulation of ICAM-1

Hess, David C.; Howard, Eugene F.; Cheng, Charles Y.; Carroll, James E.; Hill, W. David

doi:10.1161/01.str.31.5.1179

Cited by 29 publications

(38 citation statements)

References 30 publications

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“…Our results with isolated cerebral arteries are supported by the findings obtained from cultured cerebral endothelial cells. 20,44 Although time of NF-B activation may vary from minutes to hours or slower depending on cell types and stimuli, the time course of this study is consistent with that demonstrated in cultured cerebral endothelial cells, in which activation of NF-B occurs as early as 15 to 30 minutes after H/R. 20 We are aware that no direct measurement of NF-kB activation is a limitation of this study.…”

Section: Discussionsupporting

confidence: 80%

NF-κB Activation Plays a Role in Superoxide-Mediated Cerebral Endothelial Dysfunction After Hypoxia/Reoxygenation

Xie

Ray

Short

2005

Stroke

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Background and Purpose-Cerebral vascular injury occurs in response to hypoxia/reoxygenation (H/R). However, the cellular signaling pathways that regulate this event remain unclear. The present study was designed to determine whether reactive oxygen species (ROS) mediate endothelial dysfunction after H/R in cerebral resistance arteries and, if so, the relative contribution of ROS, NADPH oxidase, and a nuclear factor-B (NF-B) pathway. Methods-Arterial diameter and intraluminal pressure were simultaneously measured on rat posterior cerebral arteries (PCA). Superoxide was measured by 5-mol/L lucigenin-enhanced chemiluminescence. Results-Hypoxia/reoxygenation selectively inhibited cerebral vasodilation to the endothelium-dependent agonist acetylcholine (Ach) (0.01 to 10 mol/L) by Ϸ50%. Impaired vasodilation after H/R was reversed by 2,2,6,6-tetramethylpiperidine-N-oxyl (Tempo) (100 mol/L), a cell-permeable superoxide dismutase mimetic, and partially by ebselen (10 mol/L), a peroxynitrite scavenger. H/R-impaired vasodilation to Ach was also preserved by apocynin (1 mmol/L), a specific inhibitor for NADPH oxidase. Correspondingly, H/R significantly increased lucigenin-detectable superoxide, which was reduced by either Tempo or apocynin, but not by allopurinol (10 mol/L), an inhibitor of xanthine oxidase. Finally, the NF-B inhibitors helenalin (10 mol/L) and MG-132 (1 mol/L) independently antagonized H/R-impaired Ach-induced vasodilation without affecting dilator response to sodium nitroprusside, an endothelium-independent vasodilator. Conclusions-These results indicate that superoxide mediates cerebral endothelial dysfunction after hypoxia/reoxygenation largely via activation of NADPH oxidase and possibly activation of NF-B pathway.

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Section: Discussionsupporting

confidence: 80%

NF-κB Activation Plays a Role in Superoxide-Mediated Cerebral Endothelial Dysfunction After Hypoxia/Reoxygenation

Xie

Ray

Short

2005

Stroke

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“…Furthermore, when administered for either primary or secondary prevention of coronary heart disease, statins effectively reduce coronary morbidity and mortality [41]. Moreover, statins are effective in reducing the risk of cerebrovascular events [42,43] as well as total mortality [44].…”

Section: Lipid-lowering Drugsmentioning

confidence: 99%

Microsomal Transfer Protein Inhibitors, New Approach for Treatment of Familial Hypercholesterolemia, Review of the Literature, Original Findings, and Clinical Significance

Kolovou

Vasiliadis

Gontoras

et al. 2015

Cardiovascular Therapeutics

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SUMMARYThe genetic causes of cholesterol metabolism disorders usually lead to premature atherosclerosis. The most well recognized genetically caused hypercholesterolemia is familial hypercholesterolemia. Although the disease is well known, as the discovery of low-density lipoprotein receptor, the classical treatment with lipid-lowering drugs (statins, fibrates, ezetimibe, colesevelam) is still not adequate and new options are seeking. This review is an attempt to analyze the microsomal transfer protein (MTP) inhibitors as a new approach for treatment of familial hypercholesterolemia, to reviews the literature according to MTP inhibitors and finally to provide original findings.

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“…For example, intercellular adhesion molecule 1, P-selectins, and E-selectins are upregulated. [42][43][44][45] Blocking antibodies against these molecules have been shown to suppress complement activation, also implicated in furthering neurovascular injury after stroke. 46 -50 Adhesion proteins interact with neutrophils, allowing them to penetrate into the vasculature and brain tissue.…”

Section: Subacutementioning

confidence: 99%

Targets for Vascular Protection After Acute Ischemic Stroke

Fagan

Hess²,

Hohnadel³

et al. 2004

Stroke

Self Cite

228

165

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Background— Vascular damage caused by cerebral ischemia leads to edema, hemorrhage formation, and worsened outcomes in ischemic stroke patients. Therapeutic interventions need to be developed to provide vascular protection. The purpose of this review is to identify the pathophysiologic processes involved in vascular damage after ischemia, which may lead to strategies to provide vascular protection in ischemic stroke patients. Summary of Comment— The pathologic processes caused by vascular injury after an occlusion of a cerebral artery can be separated into acute (hours), subacute (hours to days), and chronic (days to months). Targets for intervention can be identified for all 3 stages. Acutely, superoxide is the predominant mediator, followed by inflammatory mediators and proteases subacutely. In the chronic phase, proapoptotic gene products have been implicated. Conclusions— Pharmacological agents designed to target specific pathologic and protective processes affecting the vasculature should be used in clinical trials of vascular protection after acute ischemic stroke.

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Hypertonic Mannitol Loading of NF-κB Transcription Factor Decoys in Human Brain Microvascular Endothelial Cells Blocks Upregulation of ICAM-1

Abstract: Mannitol delivers phosphothiorated oligonucleotides into cultured HBMEC. An NF-kappaB decoy blocks both TNF-alpha-induced and H/R-induced ICAM-1 upregulation in HBMEC. Targeted genetic disruption of endothelial NF-kappaB activation may be of benefit in acute ischemic stroke.

Cited by 29 publications

References 30 publications

NF-κB Activation Plays a Role in Superoxide-Mediated Cerebral Endothelial Dysfunction After Hypoxia/Reoxygenation

NF-κB Activation Plays a Role in Superoxide-Mediated Cerebral Endothelial Dysfunction After Hypoxia/Reoxygenation

Microsomal Transfer Protein Inhibitors, New Approach for Treatment of Familial Hypercholesterolemia, Review of the Literature, Original Findings, and Clinical Significance

Targets for Vascular Protection After Acute Ischemic Stroke

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