Endothelial NADPH oxidases: which NOX to target in vascular disease?

Drummond, Grant Raymond; Sobey, Christopher G.

doi:10.1016/j.tem.2014.06.012

Cited by 275 publications

(267 citation statements)

References 128 publications

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“…Indeed, the analysis of the initial 45 214 PCET-CpG set revealed that known players in cellular defense against oxidation-that is, members of the glutathione peroxidase (GPX), superoxide dismutase (SOD), thioredoxin reductase (TXNRD), and thioredoxin (TXN) families [24][25][26] were hypomethylated at their promoters with increasing PCET. Noticeably, within the 4 endothelial NADPH oxidases (NOX), the only atheroprotective isoform is NOX4, 27 which was the only NOX gene undergoing promoter hypomethylation in our sample. Importantly, the promoter of ten-eleven translocation-2 (TET2) was hypomethylated with increasing PCET.…”

Section: Dna Methylation Variation After Cerebrovascular Eventsmentioning

confidence: 79%

DNA Methylation Dynamics in Human Carotid Plaques After Cerebrovascular Events

Zaina¹,

Gonçalves²,

Carmona³

et al. 2015

ATVB

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Recently, our high-coverage epigenomics study of the human aorta and carotid arteries has identified atherosclerosis-specific DNA methylation profiles that are lesion gradeindependent and are, therefore, established relatively early © 2015 American Heart Association, Inc. Objective-To understand whether cerebrovascular events, a major complication of atherosclerosis, are associated with any specific DNA methylation changes in the carotid plaque. Approach and Results-We profiled the DNA methylomes of human symptomatic carotid plaques obtained from patients who had cerebrovascular events (n=19) and asymptomatic counterparts (n=19) with a high-density microarray (≈485 000 CpG sites, Illumina), and crossed DNA methylation data with RNAseq-based expression data from an independent symptomatic carotid plaque set (n=8). Few (30) CpGs showed a significant (P<0.05; absolute Delta-Beta, >0.20) differential methylation between the 2 groups. Within symptomatic carotid plaques, DNA methylation correlated significantly with postcerebrovascular event time (range, 3-45 days; r-value range, −0.926 to 0.857; P<0.05) for ≈45 000 CpGs, the vast majority of which became hypomethylated with increasing postcerebrovascular event time. Hypomethylation was not due to erasure of the gene-body and CG-poor region hypermethylation that accompany the progression of stable lesions, but rather targeted promoters and CpG islands. Noticeably, promoter hypomethylation and increased expression of genes involved in the inhibition of the inflammatory response, defense against oxidative stress, and active DNA demethylation were observed with increasing postcerebrovascular event time. Concomitantly, histological changes consistent with phagocyte-driven plaque healing were observed. Conclusions-Weak changes in the DNA methylome distinguish symptomatic from asymptomatic plaques, but a widespread demethylation resulting in permissive transcriptional marks at atheroprotective gene promoters is established in plaques after a cerebrovascular event, thus mirroring previous observations that ruptured plaques tend to revert to a stable structure. The identified loci are candidate targets to accelerate the pace of carotid plaque stabilization. (Arterioscler Thromb Vasc

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Section: Dna Methylation Variation After Cerebrovascular Eventsmentioning

confidence: 79%

DNA Methylation Dynamics in Human Carotid Plaques After Cerebrovascular Events

Zaina¹,

Gonçalves²,

Carmona³

et al. 2015

ATVB

View full text Add to dashboard Cite

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“…Sheehan and co-workers reported that these double knockout mice developed fewer and smaller atherosclerotic lesions [126], while another group determined that the lesions were even larger than those found on apoE-/-mice [115].…”

Section: Nadph Oxidasementioning

confidence: 99%

“…The cells involved in atherosclerosis express NADPH oxidases. Endothelial cells express four NADPH oxidase isoforms, out of which NOX1, 2, and 5 trigger endothelial dysfunction and vascular disease, and NOX4 generates hydrogen peroxide and exerts protective effects on the vessel wall [115]. In macrophages, Nox1 and Nox4 are inducible and mediate LDL oxidation [116].…”

Section: Nadph Oxidasementioning

confidence: 99%

Enzymatic Targets in Atherosclerosis

Fuior¹,

Trusca²,

Roman³

et al. 2015

J Mol Genet Med

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Atherosclerosis, a prime cause of mortality across the developed societies, was targeted by diverse therapeutic strategies. These evolved in response to the complex etiology and evolution of the disease. Many enzymes are associated with atherosclerosis, either in the main stream of lipid biosynthesis and transport or in the collateral and intertwined pathways of oxidative stress, inflammation, vascular remodeling or chromatin stability and are therefore revised herein. Enzyme exploration led to important developments. At the beginning, there were the statins, derived as inhibitors of hydroxy-methyl-glutaryl CoA (HMG-CoA) reductase, currently used widely to decrease lipid levels. At the other end, the inhibitors of the recently discovered proprotein convertase subtilisin/kexin type 9 (PCSK9) are awaiting the validation in clinical trials with great hopes for the future. In between, one can find some palliatives, as aspirin, an inhibitor of cyclooxygenase (COX), but also many invalidated candidates. Classical pharmacological data and newer approaches, like genetic knockouts in murine atherosclerosis models, are reviewed in order to appreciate the involvement of a particular enzyme in atherogenesis. However, the pursuit of an efficacious drug has been long and, in many cases, disappointing. Conclusions can be drawn from the overview of both successes and failures, in a quest for the best.

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“…Being similar to leukocyte enzymes, the oxidases were shown to play an important role in maintaining functionality of the cell types and thereby vascular homeostasis (Gorlach et al, 2000). Since then, the indepth functions of the NOX proteins have been presented in excellent reviews (Lambeth, 2004;Streeter et al, 2013;Drummond and Sobey, 2014). The NOX complex comprises several subunits, including members of the family of NOX proteins, responsible for the generation of superoxide or other reactive oxygen species (ROS).…”

Section: Role Of Rac1 In the Vasculature Endothelial Cellsmentioning

confidence: 99%

The Ins and Outs of Small GTPase Rac1 in the Vasculature

Marinković

Heemskerk

Buul

et al. 2015

J Pharmacol Exp Ther

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The Rho family of small GTPases forms a 20-member family within the Ras superfamily of GTP-dependent enzymes that are activated by a variety of extracellular signals. The most well known Rho family members are RhoA (Ras homolog gene family, member A), Cdc42 (cell division control protein 42), and Rac1 (Ras-related C3 botulinum toxin substrate 1), which affect intracellular signaling pathways that regulate a plethora of critical cellular functions, such as oxidative stress, cellular contacts, migration, and proliferation. In this review, we describe the current knowledge on the role of GTPase Rac1 in the vasculature. Whereas most recent reviews focus on the role of vascular Rac1 in endothelial cells, in the present review we also highlight the functional involvement of Rac1 in other vascular cells types, namely, smooth muscle cells present in the media and fibroblasts located in the adventitia of the vessel wall. Collectively, this overview shows that Rac1 activity is involved in various functions within one cell type at distinct locations within the cell, and that there are overlapping but also cell type-specific functions in the vasculature. Chronically enhanced Rac1 activity seems to contribute to vascular pathology; however, Rac1 is essential to vascular homeostasis, which makes Rac1 inhibition as a therapeutic option a delicate balancing act.

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Endothelial NADPH oxidases: which NOX to target in vascular disease?

Cited by 275 publications

References 128 publications

DNA Methylation Dynamics in Human Carotid Plaques After Cerebrovascular Events

DNA Methylation Dynamics in Human Carotid Plaques After Cerebrovascular Events

Enzymatic Targets in Atherosclerosis

The Ins and Outs of Small GTPase Rac1 in the Vasculature

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