Evidence map›Paper›PMID 26715682›Full record

ArticleArteriosclerosis, thrombosis, and vascular biology2016

Reactive Oxygen Species Can Provide Atheroprotection via NOX4-Dependent Inhibition of Inflammation and Vascular Remodeling.

Stephen P Gray, Elyse Di Marco, Kit Kennedy, Phyllis Chew, Jun Okabe, Assam El-Osta, Anna C Calkin, Erik A L Biessen, Rhian M Touyz, Mark E Cooper and 2 more

Open access · bronzeAbstract read
PubMed Publisher
In one paragraph

Article in Arteriosclerosis, thrombosis, and vascular biology, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 106 papers.

0numbers the graph read from it
0cells of the map it votes in
106citing papers in PubMed
9.5field-weighted citation impact, top 1% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

106 citing papers in PubMed, 187 citations in OpenAlex.

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  20. Endothelial Reprogramming in Atherosclerosis.Bioengineering (Basel, Switzerland) · 2024
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46 more citing papers are in PubMed but not listed here.

4 · The record

Corrections and comments

5 · Who and what money

Authors and funding

12 authors at 3 institutions in 3 countries.

Stephen P GrayFrom the Diabetic Complications Laboratory (S.P.G., E.D.M., K.K., P.C., M.E.C., K.A.M.J.-D.), Epigenetics Laboratory (J.O., A.E.-O.), and Diabetes and Dyslipidaemia Group (A.C.C.), Baker IDI Heart and Diabetes Institute, Melbourne, Australia; Faculty of Medicine, Monash University, Melbourne, Australia (S.P.G., E.D.M., K.A.M.J.-D.); Department of Pathology, Maastricht University Medical Center, Maastricht, The Netherlands (E.A.L.B.); Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, United Kingdom (R.M.T.); and Department of Pharmacology, Cardiovascular Research Institute Maastricht (CARIM), Faculty of Medicine, Health, and Life Science, Maastricht University, Maastricht, The Netherlands (H.H.H.W.S.). Stephen.gray@bakeridi.edu.au.
Elyse Di MarcoFrom the Diabetic Complications Laboratory (S.P.G., E.D.M., K.K., P.C., M.E.C., K.A.M.J.-D.), Epigenetics Laboratory (J.O., A.E.-O.), and Diabetes and Dyslipidaemia Group (A.C.C.), Baker IDI Heart and Diabetes Institute, Melbourne, Australia; Faculty of Medicine, Monash University, Melbourne, Australia (S.P.G., E.D.M., K.A.M.J.-D.); Department of Pathology, Maastricht University Medical Center, Maastricht, The Netherlands (E.A.L.B.); Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, United Kingdom (R.M.T.); and Department of Pharmacology, Cardiovascular Research Institute Maastricht (CARIM), Faculty of Medicine, Health, and Life Science, Maastricht University, Maastricht, The Netherlands (H.H.H.W.S.).
Kit KennedyFrom the Diabetic Complications Laboratory (S.P.G., E.D.M., K.K., P.C., M.E.C., K.A.M.J.-D.), Epigenetics Laboratory (J.O., A.E.-O.), and Diabetes and Dyslipidaemia Group (A.C.C.), Baker IDI Heart and Diabetes Institute, Melbourne, Australia; Faculty of Medicine, Monash University, Melbourne, Australia (S.P.G., E.D.M., K.A.M.J.-D.); Department of Pathology, Maastricht University Medical Center, Maastricht, The Netherlands (E.A.L.B.); Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, United Kingdom (R.M.T.); and Department of Pharmacology, Cardiovascular Research Institute Maastricht (CARIM), Faculty of Medicine, Health, and Life Science, Maastricht University, Maastricht, The Netherlands (H.H.H.W.S.).
Phyllis ChewFrom the Diabetic Complications Laboratory (S.P.G., E.D.M., K.K., P.C., M.E.C., K.A.M.J.-D.), Epigenetics Laboratory (J.O., A.E.-O.), and Diabetes and Dyslipidaemia Group (A.C.C.), Baker IDI Heart and Diabetes Institute, Melbourne, Australia; Faculty of Medicine, Monash University, Melbourne, Australia (S.P.G., E.D.M., K.A.M.J.-D.); Department of Pathology, Maastricht University Medical Center, Maastricht, The Netherlands (E.A.L.B.); Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, United Kingdom (R.M.T.); and Department of Pharmacology, Cardiovascular Research Institute Maastricht (CARIM), Faculty of Medicine, Health, and Life Science, Maastricht University, Maastricht, The Netherlands (H.H.H.W.S.).
Jun OkabeFrom the Diabetic Complications Laboratory (S.P.G., E.D.M., K.K., P.C., M.E.C., K.A.M.J.-D.), Epigenetics Laboratory (J.O., A.E.-O.), and Diabetes and Dyslipidaemia Group (A.C.C.), Baker IDI Heart and Diabetes Institute, Melbourne, Australia; Faculty of Medicine, Monash University, Melbourne, Australia (S.P.G., E.D.M., K.A.M.J.-D.); Department of Pathology, Maastricht University Medical Center, Maastricht, The Netherlands (E.A.L.B.); Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, United Kingdom (R.M.T.); and Department of Pharmacology, Cardiovascular Research Institute Maastricht (CARIM), Faculty of Medicine, Health, and Life Science, Maastricht University, Maastricht, The Netherlands (H.H.H.W.S.).
Assam El-OstaFrom the Diabetic Complications Laboratory (S.P.G., E.D.M., K.K., P.C., M.E.C., K.A.M.J.-D.), Epigenetics Laboratory (J.O., A.E.-O.), and Diabetes and Dyslipidaemia Group (A.C.C.), Baker IDI Heart and Diabetes Institute, Melbourne, Australia; Faculty of Medicine, Monash University, Melbourne, Australia (S.P.G., E.D.M., K.A.M.J.-D.); Department of Pathology, Maastricht University Medical Center, Maastricht, The Netherlands (E.A.L.B.); Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, United Kingdom (R.M.T.); and Department of Pharmacology, Cardiovascular Research Institute Maastricht (CARIM), Faculty of Medicine, Health, and Life Science, Maastricht University, Maastricht, The Netherlands (H.H.H.W.S.).
Anna C CalkinFrom the Diabetic Complications Laboratory (S.P.G., E.D.M., K.K., P.C., M.E.C., K.A.M.J.-D.), Epigenetics Laboratory (J.O., A.E.-O.), and Diabetes and Dyslipidaemia Group (A.C.C.), Baker IDI Heart and Diabetes Institute, Melbourne, Australia; Faculty of Medicine, Monash University, Melbourne, Australia (S.P.G., E.D.M., K.A.M.J.-D.); Department of Pathology, Maastricht University Medical Center, Maastricht, The Netherlands (E.A.L.B.); Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, United Kingdom (R.M.T.); and Department of Pharmacology, Cardiovascular Research Institute Maastricht (CARIM), Faculty of Medicine, Health, and Life Science, Maastricht University, Maastricht, The Netherlands (H.H.H.W.S.).
Erik A L BiessenFrom the Diabetic Complications Laboratory (S.P.G., E.D.M., K.K., P.C., M.E.C., K.A.M.J.-D.), Epigenetics Laboratory (J.O., A.E.-O.), and Diabetes and Dyslipidaemia Group (A.C.C.), Baker IDI Heart and Diabetes Institute, Melbourne, Australia; Faculty of Medicine, Monash University, Melbourne, Australia (S.P.G., E.D.M., K.A.M.J.-D.); Department of Pathology, Maastricht University Medical Center, Maastricht, The Netherlands (E.A.L.B.); Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, United Kingdom (R.M.T.); and Department of Pharmacology, Cardiovascular Research Institute Maastricht (CARIM), Faculty of Medicine, Health, and Life Science, Maastricht University, Maastricht, The Netherlands (H.H.H.W.S.).
Rhian M TouyzFrom the Diabetic Complications Laboratory (S.P.G., E.D.M., K.K., P.C., M.E.C., K.A.M.J.-D.), Epigenetics Laboratory (J.O., A.E.-O.), and Diabetes and Dyslipidaemia Group (A.C.C.), Baker IDI Heart and Diabetes Institute, Melbourne, Australia; Faculty of Medicine, Monash University, Melbourne, Australia (S.P.G., E.D.M., K.A.M.J.-D.); Department of Pathology, Maastricht University Medical Center, Maastricht, The Netherlands (E.A.L.B.); Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, United Kingdom (R.M.T.); and Department of Pharmacology, Cardiovascular Research Institute Maastricht (CARIM), Faculty of Medicine, Health, and Life Science, Maastricht University, Maastricht, The Netherlands (H.H.H.W.S.).
Mark E CooperFrom the Diabetic Complications Laboratory (S.P.G., E.D.M., K.K., P.C., M.E.C., K.A.M.J.-D.), Epigenetics Laboratory (J.O., A.E.-O.), and Diabetes and Dyslipidaemia Group (A.C.C.), Baker IDI Heart and Diabetes Institute, Melbourne, Australia; Faculty of Medicine, Monash University, Melbourne, Australia (S.P.G., E.D.M., K.A.M.J.-D.); Department of Pathology, Maastricht University Medical Center, Maastricht, The Netherlands (E.A.L.B.); Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, United Kingdom (R.M.T.); and Department of Pharmacology, Cardiovascular Research Institute Maastricht (CARIM), Faculty of Medicine, Health, and Life Science, Maastricht University, Maastricht, The Netherlands (H.H.H.W.S.).
Harald H H W SchmidtFrom the Diabetic Complications Laboratory (S.P.G., E.D.M., K.K., P.C., M.E.C., K.A.M.J.-D.), Epigenetics Laboratory (J.O., A.E.-O.), and Diabetes and Dyslipidaemia Group (A.C.C.), Baker IDI Heart and Diabetes Institute, Melbourne, Australia; Faculty of Medicine, Monash University, Melbourne, Australia (S.P.G., E.D.M., K.A.M.J.-D.); Department of Pathology, Maastricht University Medical Center, Maastricht, The Netherlands (E.A.L.B.); Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, United Kingdom (R.M.T.); and Department of Pharmacology, Cardiovascular Research Institute Maastricht (CARIM), Faculty of Medicine, Health, and Life Science, Maastricht University, Maastricht, The Netherlands (H.H.H.W.S.).
Karin A M Jandeleit-DahmFrom the Diabetic Complications Laboratory (S.P.G., E.D.M., K.K., P.C., M.E.C., K.A.M.J.-D.), Epigenetics Laboratory (J.O., A.E.-O.), and Diabetes and Dyslipidaemia Group (A.C.C.), Baker IDI Heart and Diabetes Institute, Melbourne, Australia; Faculty of Medicine, Monash University, Melbourne, Australia (S.P.G., E.D.M., K.A.M.J.-D.); Department of Pathology, Maastricht University Medical Center, Maastricht, The Netherlands (E.A.L.B.); Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, United Kingdom (R.M.T.); and Department of Pharmacology, Cardiovascular Research Institute Maastricht (CARIM), Faculty of Medicine, Health, and Life Science, Maastricht University, Maastricht, The Netherlands (H.H.H.W.S.).
Monash University · AUMaastricht University · NLUniversity of Glasgow · GB

Funding

British Heart Foundation RG/13/7/30099
6 · The paper itself

Abstract

objectiveOxidative stress is considered a hallmark of atherosclerosis. In particular, the superoxide-generating type 1 NADPH oxidase (NOX1) has been shown to be induced and play a pivotal role in early phases of mouse models of atherosclerosis and in the context of diabetes mellitus. Here, we investigated the role of the most abundant type 4 isoform (NOX4) in human and mouse advanced atherosclerosis. APPROACH AND

resultsPlaques of patients with cardiovascular events or established diabetes mellitus showed a surprising reduction in expression of the most abundant but hydrogen peroxide (H2O2)-generating type 4 isoform (Nox4), whereas Nox1 mRNA was elevated, when compared with respective controls. As these data suggested that NOX4-derived reactive oxygen species may convey a surprisingly protective effect during plaque progression, we examined a mouse model of accelerated and advanced diabetic atherosclerosis, the streptozotocin-treated ApoE(-/-) mouse, with (NOX4(-/-)) and without genetic deletion of Nox4. Similar to the human data, advanced versus early plaques of wild-type mice showed reduced Nox4 mRNA expression. Consistent with a rather protective role of NOX4-derived reactive oxygen species, NOX4(-/-) mice showed increased atherosclerosis when compared with wild-type mice. Deleting NOX4 was associated with reduced H2O2 forming activity and attenuation of the proinflammatory markers, monocyte chemotratic protein-1, interleukin-1β, and tumor necrosis factor-α, as well as vascular macrophage accumulation. Furthermore, there was a greater accumulation of fibrillar collagen fibres within the vascular wall and plaque in diabetic Nox4(-/-)ApoE(-/-) mice, indicative of plaque remodeling. These data could be replicated in human aortic endothelial cells in vitro, where Nox4 overexpression increased H2O2 and reduced the expression of pro-oxidants and profibrotic markers. Interestingly, Nox4 levels inversely correlated with Nox2 gene and protein levels. Although NOX2 is not constitutively active unlike NOX4 and forms rather superoxide, this opens up the possibility that at least some effects of NOX4 deletion are mediated by NOX2 activation.

conclusionsThus, the appearance of reactive oxygen species in atherosclerosis is apparently not always a nondesirable oxidative stress, but can also have protective effects. Both in humans and in mouse, the H2O2-forming NOX4, unlike the superoxide-forming NOX1, can act as a negative modulator of inflammation and remodeling and convey atheroprotection. These results have implications on how to judge reactive oxygen species formation in cardiovascular disease and need to be considered in the development of NOX inhibitory drugs.

Indexed as

Oxidative StressPlaque, AtheroscleroticVascular RemodelingAnimalsAortaAortic DiseasesApolipoproteins EAtherosclerosisCase-Control StudiesCells, CulturedCytokinesDisease Models, AnimalEndothelial CellsFibrillar CollagensHumansHydrogen PeroxideApolipoproteins ECYBB protein, humanCytokinesFibrillar CollagensHydrogen PeroxideInflammation MediatorsMembrane GlycoproteinsNADH, NADPH OxidoreductasesNADPH Oxidase 1NADPH Oxidase 2NADPH Oxidase 4NADPH OxidasesNOX1 protein, mouseNOX4 protein, humanNox4 protein, mouseSuperoxidesatherosclerosisdiabetes mellitusendothelial cellsNADPH oxidasereactive oxygen species

Identifiers

PMID26715682
OpenAlexW2209633084

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.