Ang II Promotes ET-1 Production by Regulating NOX2 Activity Through Transcription Factor Oct-1

Kamhieh-Milz, Julian; Chen, Lei; Goettsch, Claudia; Pfefferkorn, Anna Maria; Hofmann, Anja; Brunssen, Coy; Müller, Gregor M.; Walther, Thomas; Ashraf, Muhammad Imtiaz; Moll, Guido; Morawietz, Henning; Witowski, Janusz; Catar, Rusan

doi:10.1161/atvbaha.122.318764

Cited by 5 publications

(16 citation statements)

References 56 publications

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“…Under pathophysiological conditions, intensified NOX2 activity promotes ET-1 production in ECs, which mediates pro-inflammatory microglia activation and neuroinflammation, involved in vascular disruption and disruption of the blood-brain barrier in neurodegenerative diseases [ 49 – 51 ]. To further explore the mechanism of NOX2 regulation of iBRB, we hypothesized that the NOX2/ET-1 axis regulates the proliferation of microglia (the principal mediator of neuroinflammation) via the MAPK signaling pathway mediating the inflammatory damage to the iBRB in pathologically H-IOP.…”

Section: Resultsmentioning

confidence: 99%

“…ET-1 concentrations were observed to be increased in separate animal models of glaucoma [ 85 – 87 ], and this peptide plays a role in hypertension-related vascular injury [ 88 , 89 ]. NOX2 activity promotes ET-1 production in ECs [ 49 ], and NOX-mediated superoxide production contributes to ET-1-dependent regulation of vascular homeostasis in physiology and disease [ 90 ]. In cardiomyocytes, mechanical stretch-released Ang II [ 91 ] induces NOX2 activation of the auto-AT1 receptor and induces ET-1 release [ 92 ].…”

Section: Discussionmentioning

confidence: 99%

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Pathological high intraocular pressure induces glial cell reactive proliferation contributing to neuroinflammation of the blood-retinal barrier via the NOX2/ET-1 axis-controlled ERK1/2 pathway

Shi,

Li,

Herb

et al. 2024

J Neuroinflammation

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Background NADPH oxidase (NOX), a primary source of endothelial reactive oxygen species (ROS), is considered a key event in disrupting the integrity of the blood-retinal barrier. Abnormalities in neurovascular-coupled immune signaling herald the loss of ganglion cells in glaucoma. Persistent microglia-driven inflammation and cellular innate immune system dysregulation often lead to deteriorating retinal degeneration. However, the crosstalk between NOX and the retinal immune environment remains unresolved. Here, we investigate the interaction between oxidative stress and neuroinflammation in glaucoma by genetic defects of NOX2 or its regulation via gp91ds-tat. Methods Ex vivo cultures of retinal explants from wildtype C57BL/6J and Nox2−/− mice were subjected to normal and high hydrostatic pressure (Pressure 60 mmHg) for 24 h. In vivo, high intraocular pressure (H-IOP) was induced in C57BL/6J mice for two weeks. Both Pressure 60 mmHg retinas and H-IOP mice were treated with either gp91ds-tat (a NOX2-specific inhibitor). Proteomic analysis was performed on control, H-IOP, and treatment with gp91ds-tat retinas to identify differentially expressed proteins (DEPs). The study also evaluated various glaucoma phenotypes, including IOP, retinal ganglion cell (RGC) functionality, and optic nerve (ON) degeneration. The superoxide (O2-) levels assay, blood-retinal barrier degradation, gliosis, neuroinflammation, enzyme-linked immunosorbent assay (ELISA), western blotting, and quantitative PCR were performed in this study. Results We found that NOX2-specific deletion or activity inhibition effectively attenuated retinal oxidative stress, immune dysregulation, the internal blood-retinal barrier (iBRB) injury, neurovascular unit (NVU) dysfunction, RGC loss, and ON axonal degeneration following H-IOP. Mechanistically, we unveiled for the first time that NOX2-dependent ROS-driven pro-inflammatory signaling, where NOX2/ROS induces endothelium-derived endothelin-1 (ET-1) overexpression, which activates the ERK1/2 signaling pathway and mediates the shift of microglia activation to a pro-inflammatory M1 phenotype, thereby triggering a neuroinflammatory outburst. Conclusions Collectively, we demonstrate for the first time that NOX2 deletion or gp91ds-tat inhibition attenuates iBRB injury and NVU dysfunction to rescue glaucomatous RGC loss and ON axon degeneration, which is associated with inhibition of the ET-1/ERK1/2-transduced shift of microglial cell activation toward a pro-inflammatory M1 phenotype, highlighting NOX2 as a potential target for novel neuroprotective therapies in glaucoma management.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Pathological high intraocular pressure induces glial cell reactive proliferation contributing to neuroinflammation of the blood-retinal barrier via the NOX2/ET-1 axis-controlled ERK1/2 pathway

Shi,

Li,

Herb

et al. 2024

J Neuroinflammation

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“…More recently, we were able to analyse the cross-talk between obesity, angiotensin II (Ang II), NOX2 and endothelin-1 (ET-1) in more detail [ 79 ]. Feeding mice a high-fat diet increased cardiac expression and plasma levels of Ang II and ET-1 in wild-type but not in Nox2-deficient animals.…”

Section: Cross-talk Of Nadph Oxidases Inflammation Hypercholesterolem...mentioning

confidence: 99%

“…Inhibition of Oct-1 by small interfering RNA reduced Ang II-induced NOX2 expression and superoxide anion production, and neutralization of superoxide by superoxide dismutase abolished Ang II-stimulated human ET1 promoter activity, pre-pro ET1 mRNA expression, and ET-1 release. In summary, Ang II may promote ET-1 production in the endothelium of obese mice in response to atherogenic diets through a mechanism that involves the transcription factor Oct-1 and the increased formation of superoxide anions by NOX2 [ 79 ].…”

Section: Cross-talk Of Nadph Oxidases Inflammation Hypercholesterolem...mentioning

confidence: 99%

Cross-Talk of NADPH Oxidases and Inflammation in Obesity

Morawietz¹,

Brendel²,

Diaba-Nuhoho

et al. 2023

Antioxidants

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Obesity is a major risk factor for cardiovascular and metabolic diseases. Multiple experimental and clinical studies have shown increased oxidative stress and inflammation linked to obesity. NADPH oxidases are major sources of reactive oxygen species in the cardiovascular system and in metabolically active cells and organs. An impaired balance due to the increased formation of reactive oxygen species and a reduced antioxidative capacity contributes to the pathophysiology of cardiovascular and metabolic diseases and is linked to inflammation as a major pathomechanism in cardiometabolic diseases. Non-alcoholic fatty liver disease is particularly characterized by increased oxidative stress and inflammation. In recent years, COVID-19 infections have also increased oxidative stress and inflammation in infected cells and tissues. Increasing evidence supports the idea of an increased risk for severe clinical complications of cardiometabolic diseases after COVID-19. In this review, we discuss the role of oxidative stress and inflammation in experimental models and clinical studies of obesity, cardiovascular diseases, COVID-19 infections and potential therapeutic strategies.

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“…We have recently characterized a pathway by which angiotensin II (Ang II) can stimulate endothelial ET-1 production. It involves the induction of nicotinamide adenine dinucleotide phosphate oxidase 2 (NOX2) expression and the production of superoxide anions that activate the ET1 promoter and increase ET1 mRNA expression and protein release [11]. In the present study, we investigated the effect of Ang II on ECE-1.…”

Section: Introductionmentioning

confidence: 99%

The Role of NOX2-Derived Reactive Oxygen Species in the Induction of Endothelin-Converting Enzyme-1 by Angiotensin II

Adu-Gyamfi,

Goettsch,

Kamhieh-Milz

et al. 2024

Antioxidants

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Endothelin-1 is a key regulator of vascular tone and blood pressure in health and disease. We have recently found that ET-1 production in human microvascular endothelial cells (HMECs) can be promoted by angiotensin II (Ang II) through a novel mechanism involving octamer-binding transcription factor-1 (Oct-1), NADPH oxidase-2 (NOX2), and superoxide anions. As the formation of bioactive ET-1 also depends on endothelin-converting enzyme-1 (ECE-1), we investigated the transcriptional regulation of the ECE1 gene. We found that exposure of HMECs to Ang II resulted in a concentration- and time-dependent increase in ECE1 mRNA expression. Pharmacological inhibition of ECE-1 reduced Ang II-stimulated ET-1 release to baseline values. The effect of Ang II on ECE1 mRNA expression was associated with Oct-1 binding to the ECE1 promoter, resulting in its increased activity. Consequently, the Ang II-stimulated increase in ECE1 mRNA expression could be prevented by siRNA-mediated Oct-1 inhibition. It could also be abolished by silencing the NOX2 gene and neutralizing superoxide anions with superoxide dismutase. In mice fed a high-fat diet, cardiac expression of Ece1 mRNA increased in wild-type mice but not in Nox2-deficient animals. It can be concluded that Ang II engages Oct-1, NOX2, and superoxide anions to stimulate ECE1 expression in the endothelium.

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Ang II Promotes ET-1 Production by Regulating NOX2 Activity Through Transcription Factor Oct-1

Cited by 5 publications

References 56 publications

Pathological high intraocular pressure induces glial cell reactive proliferation contributing to neuroinflammation of the blood-retinal barrier via the NOX2/ET-1 axis-controlled ERK1/2 pathway

Pathological high intraocular pressure induces glial cell reactive proliferation contributing to neuroinflammation of the blood-retinal barrier via the NOX2/ET-1 axis-controlled ERK1/2 pathway

Cross-Talk of NADPH Oxidases and Inflammation in Obesity

The Role of NOX2-Derived Reactive Oxygen Species in the Induction of Endothelin-Converting Enzyme-1 by Angiotensin II

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