Stabilization of p22phox by Hypoxia Promotes Pulmonary Hypertension

Zhang, Zuwen; Trautz, Benjamin; Kračun, Damir; Vogel, Frederick; Weitnauer, Michael; Hochkogler, K; Petry, Andreas; Görlach, Agnes

doi:10.1089/ars.2017.7482

Cited by 14 publications

(10 citation statements)

References 56 publications

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“…The main isoforms of Nox in endothelial cells are Nox1, Nox2, Nox4, and Nox5 and are the major sources of endothelial cell-derived ROS ( Touyz et al, 2011 ; Wingler et al, 2011 ; Cat et al, 2013 ). It has been confirmed that AngII activates Nox and promotes the production of ROS ( Qiu et al, 2015 ; Liu et al, 2016 ; Zhang et al, 2019 ). It is believed to increase ROS production via the Nox families by increasing their protein expression as well as their catalytic activity ( Zhang et al, 2019 ).…”

Section: Discussionmentioning

confidence: 88%

“…It has been confirmed that AngII activates Nox and promotes the production of ROS ( Qiu et al, 2015 ; Liu et al, 2016 ; Zhang et al, 2019 ). It is believed to increase ROS production via the Nox families by increasing their protein expression as well as their catalytic activity ( Zhang et al, 2019 ).…”

Section: Discussionmentioning

confidence: 88%

“…NADPH oxidase is the main source of ROS in endothelial cells exposed to AngII ( Cat et al, 2013 ). There have been reports suggest that the p22phox subunit is critical for the activation of Noxs except Nox5 and duox1/2 ( Petry et al, 2010 ), and AngII increased the expression of p22phox and induced oxidative stress in the lungs and hearts of mice with hypoxia-induced pulmonary hypertension ( Zhang et al, 2019 ). Therefore, we measured the protein expression level of p22phox in HUVECs.…”

Section: Resultsmentioning

confidence: 99%

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Angiotensin II Decreases Endothelial Nitric Oxide Synthase Phosphorylation via AT1R Nox/ROS/PP2A Pathway

Ding

Jiang

et al. 2020

Front. Physiol.

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Increasing evidences suggest that angiotensin (Ang) II participates in the pathogenesis of endothelial dysfunction (ED) through multiple signaling pathways, including angiotensin type 1 receptor (AT 1 R) mediated NADPH oxidase (Nox)/reactive oxygen species (ROS) signal transduction. However, the detailed mechanism is not completely understood. In this study, we reported that AngII/AT 1 R-mediated activated protein phosphatase 2A (PP2A) downregulated endothelial nitric oxide synthase (eNOS) phosphorylation via Nox/ROS pathway. AngII treatment reduced the levels of phosphorylation of eNOS Ser1177 and nitric oxide (NO) content along with phosphorylation of PP2Ac (PP2A catalytic subunit) Tyr307, meanwhile increased the PP2A activity and ROS production in human umbilical vein endothelial cells (HUVECs). These changes could be impeded by AT 1 R antagonist candesartan (CAN). The pretreatment of 10 −8 M PP2A inhibitor okadaic acid (OA) reversed the levels of eNOS Ser1177 and NO content. Similar effects of AngII on PP2A and eNOS were also observed in the mesenteric arteries of Sprague-Dawley rats subjected to AngII infusion via osmotic minipumps for 2 weeks. We found that the PP2A activity was increased, but the levels of PP2Ac Tyr307 and eNOS Ser1177 as well as NO content were decreased in the mesenteric arteries. The pretreatments of antioxidant N-acetylcysteine (NAC) and apocynin (APO) abolished the drop of the levels of PP2Ac Tyr307 and eNOS Ser1177 induced by AngII in HUVECs. The knockdown of p22phox by small interfering RNA (siRNA) gave rise to decrement of ROS production and increment of the levels of PP2Ac Tyr307 and eNOS Ser1177. These results indicated that AngII/AT 1 R pathway activated PP2A by downregulating its catalytic subunit Tyr307 phosphorylation, which relies on the Nox activation and ROS production. In summary, our findings indicate that AngII downregulates PP2A catalytic subunit Tyr307 phosphorylation to activate PP2A via AT 1 R-mediated Nox/ROS signaling pathway. The activated PP2A further decreases levels of eNOS Ser1177 phosphorylation and NO content leading to endothelial dysfunction.

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Section: Discussionmentioning

confidence: 88%

Section: Discussionmentioning

confidence: 88%

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

Angiotensin II Decreases Endothelial Nitric Oxide Synthase Phosphorylation via AT1R Nox/ROS/PP2A Pathway

Ding

Jiang

et al. 2020

Front. Physiol.

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“…In fact, as indicated in this study, chronic hypoxia results in pulmonary vascular remodeling and right ventricular hypertrophy. This has not only been associated with an increase in pulmonary vascular resistance and right ventricular pressure due to increased afterload in chronic hypoxic mice 21,22 , but has also been associated with a decreased ability of conductance vessels to store and deliver the entire stroke volume of the right ventricle and ultimately resulting in a loss of pulmonary flow during diastole 23 . PTT values (or CPTT - Cardiopulmonary Transit Times) have been previously studied in humans by using the first pass radionuclide cardiography technique 24 .…”

Section: Discussionmentioning

confidence: 99%

“…Positive and negative controls were included with each run. For evaluation of each lung, small α-smooth muscle actin positive vessels less than 30 µm were identified in three randomly selected regions of interest covering an area of 1 mm 2 each 22 .…”

Section: Methodsmentioning

confidence: 99%

Volumetric optoacoustic tomography enables non-invasive in vivo characterization of impaired heart function in hypoxic conditions

Ivanković

Deán‐Ben

Lin

et al. 2019

Sci Rep

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exposure to chronic hypoxia results in pulmonary hypertension characterized by increased vascular resistance and pulmonary vascular remodeling, changes in functional parameters of the pulmonary vasculature, and right ventricular hypertrophy, which can eventually lead to right heart failure. The underlying mechanisms of hypoxia-induced pulmonary hypertension have still not been fully elucidated while no curative treatment is currently available. Commonly employed pre-clinical analytic methods are largely limited to invasive studies interfering with cardiac tissue or otherwise ex vivo functional studies and histopathology. In this work, we suggest volumetric optoacoustic tomography (VOT) for non-invasive assessment of heart function in response to chronic hypoxia. Mice exposed for 3 consecutive weeks to normoxia or chronic hypoxia were imaged in vivo with heart perfusion tracked by VOT using indocyanide green contrast agent at high temporal (100 Hz) and spatial (200 µm) resolutions in 3D. Unequivocal difference in the pulmonary transit time was revealed between the hypoxic and normoxic conditions concomitant with the presence of pulmonary vascular remodeling within hypoxic models. Furthermore, a beat-to-beat analysis of the volumetric image data enabled identifying and characterizing arrhythmic events in mice exposed to chronic hypoxia. The newly introduced noninvasive methodology for analysis of impaired pulmonary vasculature and heart function under chronic hypoxic exposure provides important inputs into development of early diagnosis and treatment strategies in pulmonary hypertension. Pulmonary hypertension (PH) is a disorder characterized by pulmonary vascular remodeling, right ventricular hypertrophy and increased pulmonary arterial pressure. PH has been associated with various disorders while, according to the recent WHO classification, it is regarded as a separate entity when associated with hypoxia or chronic diseases of the respiratory system 1. The latter include chronic obstructive pulmonary disease (COPD), interstitial lung diseases, sleep disordered breathing, but also chronic exposure to high altitude and some rare neonatal diseases 2,3. Murine models have been widely used to gain deeper insight into lung-heart interactions under chronic hypoxic conditions 4. The hypoxia-inducible factor (HIF) has been highly implicated in the development of PH 5 where several preclinical studies focus on the molecular mechanisms of HIF and its role in PH 6-9. However, there is a lack of direct functional studies of the heart in response to chronic hypoxia. Methods for assessing pulmonary and cardiac structural alterations in PH are usually limited to histopathological ex vivo analyses looking at right ventricular (RV) hypertrophy and pulmonary vasculature changes. RV catheterization is an invasive in vivo procedure to measure pressure differences as a surrogate parameter of increased pulmonary arterial pressure 10-13 .

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NADPH-Oxidasen und HIF: zentrale Elemente der Redoxhomöostase

Petry

Görlach

2021

Biospektrum

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Reactive oxygen species (ROS) are not only toxic agents but also potent signaling molecules. NADPH oxidases are the sole enzymes to generate ROS playing an important role in redox signaling. They closely interact in several ways with hypoxia-inducible transcription factors of the HIF family. This signaling network is active under normoxic and hypoxic conditions as an important regulator of redox homeostasis. Members of the NADPH oxidases-HIF axis appear as interesting therapeutic targets for various disorders characterized by an impaired redox homeostasis.

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Stabilization of p22phox by Hypoxia Promotes Pulmonary Hypertension

Abstract: p22phox-dependent NADPH oxidases contribute to the pathophysiology of PH induced by hypoxia.

Cited by 14 publications

References 56 publications

Angiotensin II Decreases Endothelial Nitric Oxide Synthase Phosphorylation via AT1R Nox/ROS/PP2A Pathway

Angiotensin II Decreases Endothelial Nitric Oxide Synthase Phosphorylation via AT1R Nox/ROS/PP2A Pathway

Volumetric optoacoustic tomography enables non-invasive in vivo characterization of impaired heart function in hypoxic conditions

NADPH-Oxidasen und HIF: zentrale Elemente der Redoxhomöostase

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