Nox4 is a Novel Inducible Source of Reactive Oxygen Species in Monocytes and Macrophages and Mediates Oxidized Low Density Lipoprotein–Induced Macrophage Death

Lee, Chi Fung; Qiao, Mu; Schröder, Katrin; Zhao, Qiu; Asmis, Reto

doi:10.1161/circresaha.109.215392

Cited by 147 publications

(139 citation statements)

References 50 publications

(59 reference statements)

Supporting

Mentioning

132

Contrasting

Order By: Relevance

“…We showed that in mice the chemotactic activity of monocytes increases with rising levels of hyperglycemia and hyperlipidemia and is associated with increased macrophage recruitment and accelerated atherosclerotic lesion formation (18). We further demonstrated that metabolic stress induces the expression of Nox4, an inducible Nox family member that we identified in monocytes and macrophages (19) and which plays a critical role in monocyte priming by metabolic stress (17). The aim of this study was to elucidate the mechanisms underlying the conversion of monocytes into this hypermigratory, proatherogenic phenotype induced by metabolic stress and to identify the redoxsensitive pathways targeted by Nox4-derived ROS in primed monocytes.…”

Section: Discussionmentioning

confidence: 55%

“…S4) therefore may be an underestimation of total MKP-1 degradation triggered by metabolic stress. Increasing Grx1 activity also protected monocytes from converting into the hyperadhesive ( Metabolic stress in monocytes induces Nox4 (17), an inducible NADPH oxidase (Nox) family member we identified in monocytes and macrophages (19), and thereby promotes the S-glutathionylation of actin (17). To examine whether Nox4-derived ROS also mediate the S-glutathionylation, inactivation, and degradation of MKP-1, THP-1 monocytes were transfected with siRNA directed against Nox4 and then were exposed to metabolic stress, i.e., LDL plus high glucose.…”

Section: Metabolic Stress Promotes S-glutathionylation and Subsequentmentioning

confidence: 92%

“…In dyslipidemic and in diabetic mice the increased responsiveness of monocytes to chemokine-induced migration correlated with the level of intracellular thiol oxidative stress and was a strong predictor of both lesion size and macrophage content of atherosclerotic plaques (17,18). Monocyte priming by metabolic stress is mediated by the induction of Nox4, an NADPH oxidase recently identified in monocytes and macrophages (19). We also showed that the increased production of Nox4-derived H 2 O 2 targets reactive protein thiols and promotes protein S-glutathionylation, i.e., the formation of mixed disulfides between protein cysteine residues and glutathione (GSH).…”

mentioning

confidence: 97%

See 2 more Smart Citations

Redox regulation of MAPK phosphatase 1 controls monocyte migration and macrophage recruitment

Kim¹,

Ullevig

Zamora³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

104

125

View full text Add to dashboard Cite

Monocytic adhesion and chemotaxis are regulated by MAPK pathways, which in turn are controlled by redox-sensitive MAPK phosphatases (MKPs). We recently reported that metabolic disorders prime monocytes for enhanced recruitment into vascular lesions by increasing monocytes' responsiveness to chemoattractants. However, the molecular details of this proatherogenic mechanism were not known. Here we show that monocyte priming results in the S-glutathionylation and subsequent inactivation and degradation of MKP-1. Chronic exposure of human THP-1 monocytes to diabetic conditions resulted in the loss of MKP-1 protein levels, the hyperactivation of ERK and p38 in response to monocyte chemoattractant protein-1 (MCP-1), and increased monocyte adhesion and chemotaxis. Knockdown of MKP-1 mimicked the priming effects of metabolic stress, whereas MKP-1 overexpression blunted both MAPK activation and monocyte adhesion and migration induced by MCP-1. Metabolic stress promoted the Sglutathionylation of MKP-1, targeting MKP-1 for proteasomal degradation. Preventing MKP-1 S-glutathionylation in metabolically stressed monocytes by overexpressing glutaredoxin 1 protected MKP-1 from degradation and normalized monocyte adhesion and chemotaxis in response to MCP-1. Blood monocytes isolated from diabetic mice showed a 55% reduction in MKP-1 activity compared with nondiabetic mice. Hematopoietic MKP-1 deficiency in atherosclerosis-prone mice mimicked monocyte priming and dysfunction associated with metabolic disorders, increased monocyte chemotaxis in vivo, and accelerated atherosclerotic lesion formation. In conclusion, we identified MKP-1 as a central redox-sensitive regulator of monocyte adhesion and migration and showed that the loss of MKP-1 activity is a critical step in monocyte priming and the metabolic stress-induced conversion of blood monocytes into a proatherogenic phenotype.M etabolic disorders such as obesity and diabetes are associated with a state of chronic, low-grade inflammation (1, 2), which appears to contribute to the development of micro-and macrovascular complications such as atherosclerosis, nephropathy, and retinopathy (3-5). The cellular and molecular mechanisms involved in chronic inflammation associated with metabolic disorders are not yet fully understood, but the recruitment of blood monocytes to sites of vascular injury appears to play a central and rate-limiting role in all these complications. Metabolic disorders impact blood vessels at multiple levels, including lipid depositions, endothelial injury, and smooth muscle cell proliferation and migration, which individually or in concert initiate monocyte recruitment and promote vascular inflammation (6, 7). However, metabolic disorders also appear to affect blood monocytes directly. A number of studies reported that monocytes both in patients with metabolic disorders and in dyslipidemic or diabetic mice undergo phenotypical and functional changes that may contribute directly to the development and progression of chronic inflammatory vascular diseases (8-13)...

show abstract

Section: Discussionmentioning

confidence: 55%

Section: Metabolic Stress Promotes S-glutathionylation and Subsequentmentioning

confidence: 92%

mentioning

confidence: 97%

See 1 more Smart Citation

Redox regulation of MAPK phosphatase 1 controls monocyte migration and macrophage recruitment

Kim¹,

Ullevig

Zamora³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

104

125

View full text Add to dashboard Cite

show abstract

“…Treatment of endothelial cells with NOX4 siRNA decreased LPS induced migration and adhesion of monocytes by 36% and 52%, respectively (335). Increased NOX4 activity is also a reported risk factor in the progression of type-2 diabetic nephropathy, stroke, pulmonary fibrosis, and atherosclerotic lesions (11,145,219,240,331,382). However, the contradictory reports in the literature suggest that NOX4 is a vascular protective enzyme rather than a destructive one (415).…”

Section: A Nadph Oxidase-derived Ros In Inflammationmentioning

confidence: 99%

Reactive Oxygen Species in Inflammation and Tissue Injury

Mittal

Siddiqui

Tran

et al. 2014

Antioxidants & Redox Signaling

3,471

2,424

View full text Add to dashboard Cite

Reactive oxygen species (ROS) are key signaling molecules that play an important role in the progression of inflammatory disorders. An enhanced ROS generation by polymorphonuclear neutrophils (PMNs) at the site of inflammation causes endothelial dysfunction and tissue injury. The vascular endothelium plays an important role in passage of macromolecules and inflammatory cells from the blood to tissue. Under the inflammatory conditions, oxidative stress produced by PMNs leads to the opening of inter-endothelial junctions and promotes the migration of inflammatory cells across the endothelial barrier. The migrated inflammatory cells not only help in the clearance of pathogens and foreign particles but also lead to tissue injury. The current review compiles the past and current research in the area of inflammation with particular emphasis on oxidative stress-mediated signaling mechanisms that are involved in inflammation and tissue injury. Antioxid. Redox Signal. 20, 1126-1167.

show abstract

“…NADPH oxidases are expressed in monocytes, macrophages, and cells of the vasculature 33. NOX1 and NOX4 are expressed in the walls of the vasculature, whilst NOX2 and NOX4 are present in endothelial cells 34.…”

Section: Diabetes and Cardiovascular Diseasementioning

confidence: 99%

Recent novel approaches to limit oxidative stress and inflammation in diabetic complications

et al. 2018

View full text Add to dashboard Cite

Diabetes is considered a major burden on the healthcare system of Western and non‐Western societies with the disease reaching epidemic proportions globally. Diabetic patients are highly susceptible to developing micro‐ and macrovascular complications, which contribute significantly to morbidity and mortality rates. Over the past decade, a plethora of research has demonstrated that oxidative stress and inflammation are intricately linked and significant drivers of these diabetic complications. Thus, the focus now has been towards specific mechanism‐based strategies that can target both oxidative stress and inflammatory pathways to improve the outcome of disease burden. This review will focus on the mechanisms that drive these diabetic complications and the feasibility of emerging new therapies to combat oxidative stress and inflammation in the diabetic milieu.

show abstract

Nox4 is a Novel Inducible Source of Reactive Oxygen Species in Monocytes and Macrophages and Mediates Oxidized Low Density Lipoprotein–Induced Macrophage Death

Cited by 147 publications

References 50 publications

Redox regulation of MAPK phosphatase 1 controls monocyte migration and macrophage recruitment

Redox regulation of MAPK phosphatase 1 controls monocyte migration and macrophage recruitment

Reactive Oxygen Species in Inflammation and Tissue Injury

Recent novel approaches to limit oxidative stress and inflammation in diabetic complications

Contact Info

Product

Resources

About