scholarly journals Histone Acetyltransferase-Dependent Pathways Mediate Upregulation of NADPH Oxidase 5 in Human Macrophages under Inflammatory Conditions: A Potential Mechanism of Reactive Oxygen Species Overproduction in Atherosclerosis

2019 ◽  
Vol 2019 ◽  
pp. 1-17 ◽  
Author(s):  
Mihaela-Loredana Vlad ◽  
Simona-Adriana Manea ◽  
Alexandra-Gela Lazar ◽  
Monica Raicu ◽  
Horia Muresian ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Nadph Oxidase ◽  
Histone Acetyltransferase ◽  
Gene Promoter ◽  
Epigenetic Mechanism ◽  
Human Macrophages ◽  
Inflammatory Conditions ◽  
Gene And Protein Expression ◽  
Human Atherosclerosis ◽  
Nadph Oxidase 5

Histone acetylation plays a major role in epigenetic regulation of gene expression. Monocyte-derived macrophages express functional NADPH oxidase 5 (Nox5) that contributes to oxidative stress in atherogenesis. The mechanisms of Nox5 regulation are not entirely elucidated. The aim of this study was to investigate the expression pattern of key histone acetyltransferase subtypes (p300, HAT1) in human atherosclerosis and to determine their role in mediating the upregulation of Nox5 in macrophages under inflammatory conditions. Human nonatherosclerotic and atherosclerotic tissue samples were collected in order to determine the expression of p300 and HAT1 isoforms, H3K27ac, and Nox5. In vitro determinations were done on human macrophages exposed to lipopolysaccharide in the absence or presence of histone acetyltransferase inhibitors. Western blot, immunohistochemistry, immunofluorescence, real-time PCR, transfection, and chromatin immunoprecipitation assay were employed. The protein levels of p300 and HAT1 isoforms, H3K27ac, and Nox5 were found significantly elevated in human atherosclerotic specimens. Immunohistochemistry/immunofluorescence staining revealed that p300, HAT1, H3K27ac, H3K9ac, and Nox5 proteins were colocalized in the area of CD45+/CD68+ immune cells and lipid-rich deposits within human atherosclerotic plaques. Lipopolysaccharide induced the levels of HAT1, H3K27ac, H3K9ac, and Nox5 and the recruitment of p300 and HAT1 at the sites of active transcription within Nox5 gene promoter in cultured human macrophages. Pharmacological inhibition of histone acetyltransferase significantly reduced the Nox5 gene and protein expression in lipopolysaccharide-challenged macrophages. The overexpression of p300 or HAT1 enhanced the Nox5 gene promoter activity. The histone acetyltransferase system is altered in human atherosclerosis. Under inflammatory conditions, HAT subtypes control Nox5 overexpression in cultured human macrophages. The data suggest the existence of a new epigenetic mechanism underlying oxidative stress in atherosclerosis.

NADPH oxidase 5 expression is regulated by histone acetyltransferase 1 and P300- dependent in human macrophages

2017 ◽  
Vol 263 ◽  
pp. e87 ◽  
Author(s):  
Mihaela-Loredana Antonescu ◽  
Simona-Adriana Manea ◽  
Maya Simionescu ◽  
Adrian Manea
Keyword(s):  
Nadph Oxidase ◽  
Histone Acetyltransferase ◽  
Human Macrophages ◽  
Nadph Oxidase 5

scholarly journals Calcium Dobesilate Modulates PKCδ-NADPH Oxidase- MAPK-NF-κB Signaling Pathway to Reduce CD14, TLR4, and MMP9 Expression during Monocyte-to-Macrophage Differentiation: Potential Therapeutic Implications for Atherosclerosis

Antioxidants ◽  
2021 ◽  
Vol 10 (11) ◽  
pp. 1798
Author(s):  
Florence Njau ◽  
Hermann Haller
Keyword(s):  
Oxidative Stress ◽  
Nadph Oxidase ◽  
Inflammatory Mediators ◽  
Microvascular Complications ◽  
Ros Scavenging ◽  
Calcium Dobesilate ◽  
Macrophage Differentiation ◽  
Differentiation Potential ◽  
Human Macrophages ◽  
Mmp9 Expression

Monocyte-to-macrophage differentiation results in the secretion of various inflammatory mediators and oxidative stress molecules necessary for atherosclerosis pathogenesis. Consequently, this differentiation represents a potential clinical target in atherosclerosis. Calcium dobesilate (CaD), an established vasoactive and angioprotective drug in experimental models of diabetic microvascular complications reduces oxidative stress and inhibits inflammation via diverse molecular targets; however, its effect on monocytes/macrophages is poorly understood. In this study, we investigated the anti-inflammatory mechanism of CaD during phorbol 12-myristate 13-acetate (PMA)-induced monocyte-to-macrophage differentiation in in vitro models of sepsis (LPS) and hyperglycemia, using THP-1 monocytic cell line. CaD significantly suppressed CD14, TLR4, and MMP9 expression and activity, lowering pro-inflammatory mediators, such as IL1β, TNFα, and MCP-1. The effects of CaD translated through to studies on primary human macrophages. CaD inhibited reactive oxygen species (ROS) generation, PKCδ, MAPK (ERK1/2 and p38) phosphorylation, NOX2/p47phox expression, and membrane translocation. We used hydrogen peroxide (H2O2) to mimic oxidative stress, demonstrating that CaD suppressed PKCδ activation via its ROS-scavenging properties. Taken together, we demonstrate for the first time that CaD suppresses CD14, TLR4, MMP9, and signature pro-inflammatory cytokines, in human macrophages, via the downregulation of PKCδ/NADPH oxidase/ROS/MAPK/NF-κB-dependent signaling pathways. Our data present novel mechanisms of how CaD alleviates metabolic and infectious inflammation.

scholarly journals Ca 2+ -Dependent NOX5 (NADPH Oxidase 5) Exaggerates Cardiac Hypertrophy Through Reactive Oxygen Species Production

Hypertension ◽  
2020 ◽  
Vol 76 (3) ◽  
pp. 827-838 ◽  
Author(s):  
Guo-Jun Zhao ◽  
Chang-Ling Zhao ◽  
Shan Ouyang ◽  
Ke-Qiong Deng ◽  
Lihua Zhu ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Reactive Oxygen Species ◽  
Nadph Oxidase ◽  
Cardiac Hypertrophy ◽  
Reactive Oxygen ◽  
Contractile Dysfunction ◽  
Oxygen Species ◽  
Ang Ii ◽  
Rat Cardiomyocytes ◽  
Nadph Oxidase 5

NOX5 (NADPH oxidase 5) is a homolog of the gp91 phox subunit of the phagocyte NOX, which generates reactive oxygen species. NOX5 is involved in sperm motility and vascular contraction and has been implicated in diabetic nephropathy, atherosclerosis, and stroke. The function of NOX5 in the cardiac hypertrophy is unknown. Because NOX5 is a Ca 2+ -sensitive, procontractile NOX isoform, we questioned whether it plays a role in cardiac hypertrophy. Studies were performed in (1) cardiac tissue from patients undergoing heart transplant for cardiomyopathy and heart failure, (2) NOX5-expressing rat cardiomyocytes, and (3) mice expressing human NOX5 in a cardiomyocyte-specific manner. Cardiac hypertrophy was induced in mice by transverse aorta coarctation and Ang II (angiotensin II) infusion. NOX5 expression was increased in human failing hearts. Rat cardiomyocytes infected with adenoviral vector encoding human NOX5 cDNA exhibited elevated reactive oxygen species levels with significant enlargement and associated increased expression of ANP (atrial natriuretic peptides) and β-MHC (β-myosin heavy chain) and prohypertrophic genes ( Nppa , Nppb , and Myh7 ) under Ang II stimulation. These effects were reduced by N-acetylcysteine and diltiazem. Pressure overload and Ang II infusion induced left ventricular hypertrophy, interstitial fibrosis, and contractile dysfunction, responses that were exaggerated in cardiac-specific NOX5 trangenic mice. These phenomena were associated with increased reactive oxygen species levels and activation of redox-sensitive MAPK (mitogen-activated protein kinase). N-acetylcysteine treatment reduced cardiac oxidative stress and attenuated cardiac hypertrophy in NOX5 trangenic. Our study defines Ca 2+ -regulated NOX5 as an important NOX isoform involved in oxidative stress- and MAPK-mediated cardiac hypertrophy and contractile dysfunction.

scholarly journals NADPH Oxidase Overactivity Underlies Telomere Shortening in Human Atherosclerosis

2020 ◽  
Vol 21 (4) ◽  
pp. 1434 ◽  
Author(s):  
Álvaro Pejenaute ◽  
Adriana Cortés ◽  
Javier Marqués ◽  
Laura Montero ◽  
Óscar Beloqui ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Nadph Oxidase ◽  
Telomere Length ◽  
Surrogate Marker ◽  
Superoxide Production ◽  
Phagocytic Cells ◽  
Specific Expression ◽  
Telomere Shortening ◽  
Human Atherosclerosis ◽  
Asymptomatic Subjects

Telomere shortening and oxidative stress are involved in the pathogenesis of atherosclerosis. Different studies have shown that phagocytic NADPH oxidase is associated with this disease. This study aimed to investigate the association between phagocytic NADPH oxidase and telomere shortening in human atherosclerosis. To assess this potential association, telomere length and phagocytic NADPH oxidase activity were determined by PCR and chemiluminescence, respectively, in a population of asymptomatic subjects free of overt clinical atherosclerosis. We also measured serum 8-hydroxy-2-deoxyguanosine (8-OHdG) levels (an index of oxidative stress) and carotid intima-media thickness (IMT), a surrogate marker of atherosclerosis. After adjusting them for age and sex, telomere length inversely correlated (p < 0.05) with NADPH oxidase-mediated superoxide production, with 8-OHdG values, and with carotid IMT. Interestingly, the asymptomatic subjects with plaques have a lower telomere length (p < 0.05), and higher values of plasma 8-OHdG and superoxide production (p < 0.05). These data were confirmed in a second population in which patients with coronary artery disease showed lower telomere length and higher 8-OHdG and superoxide production than the asymptomatic subjects. In both studies, NADPH oxidase-dependent superoxide production in phagocytic cells was only due to the specific expression of the Nox2 isoform. In conclusion, these findings suggest that phagocytic NADPH oxidase may be involved in oxidative stress-mediated telomere shortening, and that this axis may be critically involved in human atherosclerosis.

scholarly journals Unique role of NADPH oxidase 5 in oxidative stress in human renal proximal tubule cells

Redox Biology ◽  
2014 ◽  
Vol 2 ◽  
pp. 570-579 ◽  
Author(s):  
Peiying Yu ◽  
Weixing Han ◽  
Van Anthony M. Villar ◽  
Yu Yang ◽  
Quansheng Lu ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Nadph Oxidase ◽  
Proximal Tubule ◽  
Renal Proximal Tubule ◽  
Proximal Tubule Cells ◽  
Unique Role ◽  
Tubule Cells ◽  
Renal Proximal Tubule Cells ◽  
Nadph Oxidase 5

scholarly journals Expression of Endothelial NOX5 Alters the Integrity of the Blood-Brain Barrier and Causes Loss of Memory in Aging Mice

Antioxidants ◽  
2021 ◽  
Vol 10 (8) ◽  
pp. 1311
Author(s):  
Adriana Cortés ◽  
Maite Solas ◽  
Álvaro Pejenaute ◽  
Miguel A. Abellanas ◽  
Marcos Garcia-Lacarte ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Nadph Oxidase ◽  
Blood Brain Barrier ◽  
Molecular Mechanisms ◽  
Cognitive Status ◽  
Brain Barrier ◽  
Morris Water Maze Test ◽  
Arterial Blood ◽  
Blood Brain ◽  
Nadph Oxidase 5

Blood-Brain barrier (BBB) disruption is a hallmark of central nervous system (CNS) dysfunction, and oxidative stress is one of the molecular mechanisms that may underlie this process. NADPH oxidases (NOX) are involved in oxidative stress-mediated vascular dysfunction and participate in the pathophysiology of its target organs. The NADPH oxidase 5 (NOX5) isoform is absent in rodents, and although little is known about the role it may play in disrupting the BBB, it has recently been implicated in experimental stroke. Our aim was to investigate the role of NADPH oxidase 5 (NOX5) in promoting vascular alterations and to identify its impact on the cognitive status of aged mice. No differences were detected in the arterial blood pressure or body weight between knock-in mice expressing endothelial NOX5 and the control mice. The Morris water maze test showed memory impairments in the aged knock-in mice expressing NOX5 compared with their control littermates. For assessing the BBB integrity, we studied the protein expression of two tight junction (TJ) proteins: Zonula occludens-1 (ZO-1) and occludin. Compared to the control animals, Aged NOX5 mice exhibited reduced levels of both proteins, demonstrating an alteration of the BBB integrity. Our data indicate that vascular NOX5 may favor behavioral changes with aging through oxidative stress-mediated BBB breakdown.

scholarly journals Near-Infrared Autofluorescence in Atherosclerosis Associates With Ceroid and Is Generated by Oxidized Lipid-Induced Oxidative Stress

2021 ◽  
Author(s):  
Mazen S. Albaghdadi ◽  
Ryutaro Ikegami ◽  
Mohamad B. Kassab ◽  
Joseph A. Gardecki ◽  
Mie Kunio ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Coronary Artery Disease ◽  
Near Infrared ◽  
Intraplaque Hemorrhage ◽  
Human Macrophages ◽  
Human Atherosclerosis ◽  
Artery Disease ◽  
And Oxidative Stress

Objective: Near-infrared autofluorescence (NIRAF) of atherosclerosis associates with intraplaque hemorrhage and is detectable in living patients with coronary artery disease. However, further mechanisms underlying NIRAF generation have not been fully characterized. Here, we investigated the role of lipids and oxidative stress in NIRAF generation in atherosclerosis and in vitro in human macrophages. Approach and Results: In N=15 human carotid endarterectomy specimens, we investigated the spatial distribution of lipid, intraplaque hemorrhage, and NIRAF (ex/em 630/650 nm). Plaque NIRAF associated with both Sudan black (SB)-positive lipids ( r =0.53, P =0.023) and GPA (glycophorin A)-positive intraplaque hemorrhage ( r =0.48, P =0.043). Plaque NIRAF also localized with lipid and specifically insoluble lipid (ceroid) and iron. Intriguingly, some NIRAF-positive areas were Sudan black-positive but GPA-negative. Studies on human macrophages investigated further the role of lipids in NIRAF generation. OxLDL (Oxidized low-density lipoprotein) and hemoglobin, but not LDL, generated NIRAF in both THP-1 cells and monocyte-derived macrophages. In oxLDL-treated THP-1 cells, higher NIRAF, lipid peroxidation products, and intracellular oxidative stress markers evolved ( P <0.001 versus LDL). The antioxidants α-tocopherol and N-acetylcysteine suppressed NIRAF generation and oxidative stress. Conclusions: In human atherosclerosis and human macrophages in vitro, NIRAF colocalizes with lipid and specifically insoluble lipid or ceroid. In vitro studies further show that oxidized LDL generates NIRAF, oxidative stress, and lipid peroxidation products. These results demonstrate a new pathway for NIRAF generation through oxidized lipid-driven oxidative stress and support ceroid as a source of NIRAF in human atherosclerosis. These findings may inform future clinical intracoronary NIRAF imaging studies of patients with coronary artery disease.

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