NOX5 variants are functionally active in endothelial cells

BelAiba, Rachida S.; Djordjevic, Talija; Petry, Andreas; Diemer, Kerstin; Bonello, Steve; Bánfi, Botond; Hess, John; Pogrebniak, Alexej; Bickel, Christian; Görlach, Agnes

doi:10.1016/j.freeradbiomed.2006.10.054

Cited by 224 publications

(243 citation statements)

References 48 publications

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“…In human endothelial cells, Ang II– and ET‐1–induced redox signaling and MAPK activation are Nox5 dependent 25. In adenovirus‐mediated Nox5 overexpression in endothelial cells, phosphorylation of p38 MAPK, JAK2 (Janus kinase 2), JNK (c‐Jun N‐terminal kinase), and ERK1/2 (extracellular signal‐regulated kinases 1 and 2) was increased,12 whereas in VSMCs, Nox5 only increased ERK1/2 phosphorylation.…”

Section: Discussionmentioning

confidence: 99%

“…Nox1 and Nox2 play a role in angiogenesis and atherosclerosis,3, 6 and Nox4 seems to be vasoprotective in ischemic and hypoxic conditions,10 but injurious in diabetes mellitus, where it promotes vascular fibrosis, diabetic nephropathy, and intravitreal neovascularization 11. Although Nox5 is expressed in mammalian vessels,12, 13, 14 there is a paucity of information on its role and biological significance in the cardiovascular system.…”

mentioning

confidence: 99%

“…This is of particular significance in vascular smooth muscle cells (VSMCs), given that increased [Ca 2+ ] i is the major trigger for vascular contraction 22, 23. Nox5 is expressed in all vascular cell types, including endothelial cells, VSMCs, and perivascular adventitial fibroblast,12, 14, 24 and plays a role in angiotensin II (Ang II)‐ and endothelin‐1 (ET‐1)‐mediated redox signaling 25. Nox5 expression is increased in human atherosclerotic and aneurysm lesions26, 27 and in kidneys from diabetic patients 28.…”

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confidence: 99%

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NADPH Oxidase 5 Is a Pro‐Contractile Nox Isoform and a Point of Cross‐Talk for Calcium and Redox Signaling‐Implications in Vascular Function

Montezano

Camargo

Persson

et al. 2018

JAHA

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BackgroundNADPH Oxidase 5 (Nox5) is a calcium‐sensitive superoxide‐generating Nox. It is present in lower forms and higher mammals, but not in rodents. Nox5 is expressed in vascular cells, but the functional significance remains elusive. Given that contraction is controlled by calcium and reactive oxygen species, both associated with Nox5, we questioned the role of Nox5 in pro‐contractile signaling and vascular function.Methods and ResultsTransgenic mice expressing human Nox5 in a vascular smooth muscle cell–specific manner (Nox5 mice) and Rhodnius prolixus, an arthropod model that expresses Nox5 endogenoulsy, were studied. Reactive oxygen species generation was increased systemically and in the vasculature and heart in Nox5 mice. In Nox5‐expressing mice, agonist‐induced vasoconstriction was exaggerated and endothelium‐dependent vasorelaxation was impaired. Vascular structural and mechanical properties were not influenced by Nox5. Vascular contractile responses in Nox5 mice were normalized by N‐acetylcysteine and inhibitors of calcium channels, calmodulin, and endoplasmic reticulum ryanodine receptors, but not by GKT137831 (Nox1/4 inhibitor). At the cellular level, vascular changes in Nox5 mice were associated with increased vascular smooth muscle cell [Ca2+]i, increased reactive oxygen species and nitrotyrosine levels, and hyperphosphorylation of pro‐contractile signaling molecules MLC20 (myosin light chain 20) and MYPT1 (myosin phosphatase target subunit 1). Blood pressure was similar in wild‐type and Nox5 mice. Nox5 did not amplify angiotensin II effects. In R. prolixus, gastrointestinal smooth muscle contraction was blunted by Nox5 silencing, but not by VAS2870 (Nox1/2/4 inhibitor).ConclusionsNox5 is a pro‐contractile Nox isoform important in redox‐sensitive contraction. This involves calcium‐calmodulin and endoplasmic reticulum–regulated mechanisms. Our findings define a novel function for vascular Nox5, linking calcium and reactive oxygen species to the pro‐contractile molecular machinery in vascular smooth muscle cells.

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

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confidence: 99%

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NADPH Oxidase 5 Is a Pro‐Contractile Nox Isoform and a Point of Cross‐Talk for Calcium and Redox Signaling‐Implications in Vascular Function

Montezano

Camargo

Persson

et al. 2018

JAHA

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“…Nox5 is directly regulated by intracellular Ca 2+ ((Ca 2+ ) i ), the binding of which induces a conformational change leading to enhanced ROS generation. 95 The functional significance of vascular Nox5 is unknown, although it has been implicated in endothelial cell proliferation, angiogenesis and migration, in platelet-derived growth factor-induced proliferation of vascular smooth muscle cells and in oxidative damage in atherosclerosis. 96,97 Vascular Nox5 is activated by thrombin, platelet-derived growth factor, Ang II and endothelin-1.…”

Section: Vascular Generation Of Rosmentioning

confidence: 99%

Reactive oxygen species and vascular biology: implications in human hypertension

2010

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Increased vascular production of reactive oxygen species (ROS; termed oxidative stress) has been implicated in various chronic diseases, including hypertension. Oxidative stress is both a cause and a consequence of hypertension. Although oxidative injury may not be the sole etiology, it amplifies blood pressure elevation in the presence of other pro-hypertensive factors. Oxidative stress is a multisystem phenomenon in hypertension and involves the heart, kidneys, nervous system, vessels and possibly the immune system. Compelling experimental and clinical evidence indicates the importance of the vasculature in the pathophysiology of hypertension and as such much emphasis has been placed on the (patho)biology of ROS in the vascular system. A major source for cardiovascular, renal and neural ROS is a family of non-phagocytic nicotinamide adenine dinucleotide phosphate (NADPH) oxidases (Nox), including the prototypic Nox2 homolog-based NADPH oxidase, as well as other Noxes, such as Nox1 and Nox4. Nox-derived ROS is important in regulating endothelial function and vascular tone. Oxidative stress is implicated in endothelial dysfunction, inflammation, hypertrophy, apoptosis, migration, fibrosis, angiogenesis and rarefaction, important processes involved in vascular remodeling in hypertension. Despite a plethora of data implicating oxidative stress as a causative factor in experimental hypertension, findings in human hypertension are less conclusive. This review highlights the importance of ROS in vascular biology and focuses on the potential role of oxidative stress in human hypertension.

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“…The presence of the short form of Nox5 was not investigated. Because of the difference in the relative expression levels of Nox1, 2, 4, and 5, and the data demonstrating the importance of Nox4 in differentiation [23] and Nox5 in human cell growth [27,28], we concentrated on examining the role of Nox5 in HASMC cell proliferation. …”

mentioning

confidence: 99%

Nox5 mediates PDGF-induced proliferation in human aortic smooth muscle cells

Jay

Papaharalambus

Seidel-Rogol

et al. 2008

Free Radical Biology and Medicine

157

137

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The proliferation of vascular smooth muscle cells is important in the pathogenesis of many vascular diseases. Reactive oxygen species (ROS) produced by NADPH oxidases in smooth muscle cells have been shown to participate in signaling cascades regulating proliferation induced by platelet-derived growth factor (PDGF), a powerful smooth muscle mitogen. We sought to determine the role of Nox5 in the regulation of PDGF-stimulated human aortic smooth muscle cell (HASMC) proliferation. Cultured HASMC were found to express four isoforms of Nox5. When HASMC stimulated with PDGF were pretreated with N-acetyl cysteine (NAC), proliferation was significantly reduced. Proliferation induced by PDGF was also heavily dependent on JAK/STAT activation, as the JAK inhibitor, AG490, was able to completely abolish PDGF-stimulated HASMC growth. Specific knockdown of Nox5 with a siRNA strategy reduced PDGF-induced HASMC ROS production and proliferation. Additionally, siRNA to Nox5 inhibited PDGF-stimulated JAK2 and STAT3 phosphorylation. ROS produced by Nox5 play an important role in PDGF-induced JAK/STAT activation and HASMC proliferation. KeywordsNADPH oxidase; reactive oxygen species; Nox5; vascular smooth muscle cells; proliferation In atherosclerosis and restenosis after percutaneous coronary intervention, cytokines elaborated by both vascular cells and cells invading the vessel wall induce vascular smooth muscle proliferation and contribute to lesion formation. In the normal vessel wall, smooth muscle cells (SMCs) maintain and regulate vascular tone. However, VSMCs change their phenotype to a synthetic, proliferative state when stimulated by a number of different growth factors.One such growth factor, platelet-derived growth factor (PDGF), is expressed by all vascular cell types [1,2] and by invading inflammatory cells, such as monocytes and lymphocytes, in atherosclerosis [1]. PDGF has long been recognized as a powerful VSMC mitogen [3] and the induction of PDGF receptors in VSMCs during atherogenesis has been demonstrated in several studies [4,5]. Blockade of PDGF, whether by anti-PDGF antibody [6][7][8], PDGF receptor antisense therapy [9,10], or chimeric knockout in mice [11], reduces lesion formation after vascular injury. Ligand binding to the PDGF receptor causes tyrosine autophosphorylation and Address correspondence to: Kathy K. Griendling, Emory University, Division of Cardiology, 319 WMB, 1639 Pierce Dr., Atlanta, GA 30322,, e-mail: kgriend@emory.edu. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. With regard to PDGF signaling, Nox5 is of particular interest because it...

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NOX5 variants are functionally active in endothelial cells

Cited by 224 publications

References 48 publications

NADPH Oxidase 5 Is a Pro‐Contractile Nox Isoform and a Point of Cross‐Talk for Calcium and Redox Signaling‐Implications in Vascular Function

NADPH Oxidase 5 Is a Pro‐Contractile Nox Isoform and a Point of Cross‐Talk for Calcium and Redox Signaling‐Implications in Vascular Function

Reactive oxygen species and vascular biology: implications in human hypertension

Nox5 mediates PDGF-induced proliferation in human aortic smooth muscle cells

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