bims-noxint Biomed News
on NADPH oxidases in tumorigenesis
Issue of 2021–08–29
nine papers selected by
Laia Caja Puigsubira, Uppsala University
  1. Expression of Endothelial NOX5 Alters the Integrity of the Blood-Brain Barrier and Causes Loss of Memory in Aging Mice.
  2. Early Cytokine-Induced Transient NOX2 Activity Is ER Stress-Dependent and Impacts β-Cell Function and Survival.
  3. Backstage players of fibrosis: NOX4, mTOR, HDAC, and S1P; companions of TGF-β.
  4. Novel Paracrine Action of Endothelium Enhances Glucose Uptake in Muscle and Fat.
  5. Human Vascular Smooth Muscle Function and Oxidative Stress Induced by NADPH Oxidase with the Clinical Implications.
  6. DPP4 inhibitor reduces portal hypertension in cirrhotic rats by normalizing arterial hypocontractility.
  7. Left Ventricular SGLT1 Protein Expression Correlates with the Extent of Myocardial Nitro-Oxidative Stress in Rats with Pressure and Volume Overload-Induced Heart Failure.
  8. Role of NADPH Oxidase-Induced Hypoxia-Induced Factor-1α Increase in Blood-Brain Barrier Disruption after 2-Hour Focal Ischemic Stroke in Rat.
  9. Role of Nox4 in high calcium-induced renal oxidative stress damage and crystal deposition.
  1. Antioxidants (Basel). 2021 Aug 20. pii: 1311. [Epub ahead of print]10(8):
    Expression of Endothelial NOX5 Alters the Integrity of the Blood-Brain Barrier and Causes Loss of Memory in Aging Mice.
    Adriana Cortés, Maite Solas, Álvaro Pejenaute, Miguel A Abellanas, Marcos Garcia-Lacarte, Maria S Aymerich, Javier Marqués, María J Ramírez, Guillermo Zalba.
      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.
    Keywords:  NOX5; Zonula occludens-1; aging; occludin; oxidative stress; tight junctions
    DOI:  https://doi.org/10.3390/antiox10081311
  2. Antioxidants (Basel). 2021 Aug 18. pii: 1305. [Epub ahead of print]10(8):
    Early Cytokine-Induced Transient NOX2 Activity Is ER Stress-Dependent and Impacts β-Cell Function and Survival.
    Eloisa A Vilas-Boas, Christopher Carlein, Lisa Nalbach, Davidson C Almeida, Emmanuel Ampofo, Angelo R Carpinelli, Leticia P Roma, Fernanda Ortis.
      In type 1 diabetes (T1D) development, proinflammatory cytokines (PIC) released by immune cells lead to increased reactive oxygen species (ROS) production in β-cells. Nonetheless, the temporality of the events triggered and the role of different ROS sources remain unclear. Isolated islets from C57BL/6J wild-type (WT), NOX1 KO and NOX2 KO mice were exposed to a PIC combination. We show that cytokines increase O2•- production after 2 h in WT and NOX1 KO but not in NOX2 KO islets. Using transgenic mice constitutively expressing a genetically encoded compartment specific H2O2 sensor, we show, for the first time, a transient increase of cytosolic/nuclear H2O2 in islet cells between 4 and 5 h during cytokine exposure. The H2O2 increase coincides with the intracellular NAD(P)H decrease and is absent in NOX2 KO islets. NOX2 KO confers better glucose tolerance and protects against cytokine-induced islet secretory dysfunction and death. However, NOX2 absence does not counteract the cytokine effects in ER Ca2+ depletion, Store-Operated Calcium Entry (SOCE) increase and ER stress. Instead, the activation of ER stress precedes H2O2 production. As early NOX2-driven ROS production impacts β-cells' function and survival during insulitis, NOX2 might be a potential target for designing therapies against early β-cell dysfunction in the context of T1D onset.
    Keywords:  ER stress; NADPH oxidase; hydrogen peroxide; insulitis; oxidative stress; proinflammatory cytokines; β-cell
    DOI:  https://doi.org/10.3390/antiox10081305
  3. Cell Signal. 2021 Aug 23. pii: S0898-6568(21)00212-6. [Epub ahead of print] 110123
    Backstage players of fibrosis: NOX4, mTOR, HDAC, and S1P; companions of TGF-β.
    Alexis Paulina Jiménez-Uribe, Tania Gómez-Sierra, Omar Emiliano Aparicio-Trejo, Marisol Orozco-Ibarra, José Pedraza-Chaverri.
      The fibrotic process could be easily defined as a pathological excess of extracellular matrix deposition, leading to disruption of tissue architecture and eventually loss of function; however, this process involves a complex network of several signal transduction pathways. Virtually almost all organs could be affected by fibrosis, the most affected are the liver, lung, skin, kidney, heart, and eyes; in all of them, the transforming growth factor-beta (TGF-β) has a central role. The canonical and non-canonical signal pathways of TGF-β impact the fibrotic process at the cellular and molecular levels, inducing the epithelial-mesenchymal transition (EMT) and the induction of profibrotic gene expression with the consequent increase in proteins such as alpha-smooth actin (α-SMA), fibronectin, collagen, and other extracellular matrix proteins. Recently, it has been reported that some molecules that have not been typically associated with the fibrotic process, such as nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 4 (NOX4), mammalian target of rapamycin (mTOR), histone deacetylases (HDAC), and sphingosine-1 phosphate (S1P); are critical in its development. In this review, we describe and discuss the role of these new players of fibrosis and the convergence with TGF-β signaling pathways, unveiling new insights into the panorama of fibrosis that could be useful for future therapeutic targets.
    Keywords:  Fibrosis; Histone deacetylases (HDAC); Mammalian target of rapamycin (mTOR); NADPH oxidase 4 (NOX4); Sphingosine-1 phosphate (S1P); TGF-β signaling pathways; Therapeutic targets
    DOI:  https://doi.org/10.1016/j.cellsig.2021.110123
  4. Circ Res. 2021 Aug 21.
    Novel Paracrine Action of Endothelium Enhances Glucose Uptake in Muscle and Fat.
    Hema Viswambharan, Nadira Yusupovna Yuldasheva, Helen Imrie, Katherine Bridge, Natalie Jayne Haywood, Anna Skromna, Karen E Hemmings, Emily Ruth Clark, V Kate Gatenby, Paul Cordell, Katie Simmons, Natallia Makava, Yilizila Abudushalamu, Naima Endesh, Jane Brown, Andrew Mn Walker, T Simon Futers, Karen E Porter, Richard M Cubbon, Khalid M Naseem, Ajay M Shah, David J Beech, Stephen Wheatcroft, Mark T Kearney, Piruthivi Sukumar.
      Rationale: A hallmark of type 2 diabetes is insulin resistance, which leads to increased endothelial cell production of superoxide and a simultaneous reduction in availability of the vasoprotective signalling radical, nitric oxide (NO). We recently demonstrated in preclinical models that type 2 diabetes simultaneously causes resistance to insulin like growth factor-1 (IGF-1) mediated glucose lowering and endothelial NO release. Objective: To examine the effect of insulin and IGF-1 resistance specifically in endothelial cells in vivo. Methods and Results: We generated mice expressing mutant IGF-1 receptors (mIGF-1R), which form non-functioning hybrid receptors with native insulin receptors (IR) and IGF-1R, directed to endothelial cells under control of the Tie2 promoter-enhancer. Despite endothelial cell insulin and IGF-1 resistance, mutant IGF-1R endothelial cell over-expressing mice (mIGFREO) had enhanced insulin and IGF-1 mediated systemic glucose disposal, lower fasting free fatty acids and triglycerides. In hyperinsulinaemic-euglycaemic clamp studies, mIGFREO had increased glucose disposal and increased glucose uptake into muscle and fat, in response to insulin. mIGFREO had increased NADPH oxidase 4 (Nox4) expression due to reduced expression of the microRNA, miR-25. Consistent with increased Nox4, mIGFREO endothelial cells generated increased hydrogen peroxide (H2O2), with no increase in superoxide. Treatment with catalase, a dismutase restored insulin tolerance to wild type levels in mIGFREO. Conclusions: Combined insulin and IGF-1 resistance restricted to the endothelium leads to a potentially favourable adaptation in contrast to pure insulin resistance, with increased Nox4-derived H2O2 generation mediating enhanced whole-body insulin sensitivity.
    DOI:  https://doi.org/10.1161/CIRCRESAHA.121.319517
  5. Cells. 2021 Jul 31. pii: 1947. [Epub ahead of print]10(8):
    Human Vascular Smooth Muscle Function and Oxidative Stress Induced by NADPH Oxidase with the Clinical Implications.
    Kazumi Takaishi, Hiroyuki Kinoshita, Shingo Kawashima, Shinji Kawahito.
      Among reactive oxygen species, superoxide mediates the critical vascular redox signaling, resulting in the regulation of the human cardiovascular system. The reduced form of nicotinamide adenine dinucleotide phosphate oxidase (NADPH oxidase, NOX) is the source of superoxide and relates to the crucial intracellular pathology and physiology of vascular smooth muscle cells, including contraction, proliferation, apoptosis, and inflammatory response. Human vascular smooth muscle cells express NOX1, 2, 4, and 5 in physiological and pathological conditions, and those enzymes play roles in most cardiovascular disorders caused by hypertension, diabetes, inflammation, and arteriosclerosis. Various physiologically active substances, including angiotensin II, stimulate NOX via the cytosolic subunits' translocation toward the vascular smooth muscle cell membrane. As we have shown, some pathological stimuli such as high glucose augment the enzymatic activity mediated by the phosphatidylinositol 3-kinase-Akt pathway, resulting in the membrane translocation of cytosolic subunits of NOXs. This review highlights and details the roles of human vascular smooth muscle NOXs in the pathophysiology and clinical aspects. The regulation of the enzyme expressed in the vascular smooth muscle cells may lead to the prevention and treatment of human cardiovascular diseases.
    Keywords:  NADPH oxidase; human vascular smooth muscle; oxidase stress
    DOI:  https://doi.org/10.3390/cells10081947
  6. Life Sci. 2021 Aug 24. pii: S0024-3205(21)00882-1. [Epub ahead of print] 119895
    DPP4 inhibitor reduces portal hypertension in cirrhotic rats by normalizing arterial hypocontractility.
    Xinxin Wang, Haitao Gu, Kaichun Li, Jiayun Lin, Yiming Zhu, Wensheng Deng.
       AIMS: Dipeptidyl peptidase-4 inhibitor (DPP4i), a new antidiabetic agent, is reported to affect the progression of chronic liver diseases. The study aims to investigate the effects of DPP4i on contractile response, splanchnic hemodynamics, and portal pressure in cirrhotic rats.
    MATERIALS AND METHODS: A rat model of carbon tetrachloride-induced cirrhosis was used in this study. Sixteen rats with cirrhosis were treated with DDP4i sitagliptin for 5 consecutive days. Portal and systemic pressures and portal blood flow were measured. Mesenteric arterioles were isolated, and concentration-response curves to norepinephrine (NE) were evaluated. The expression of NADPH oxidase (Nox)1, Nox2, Nox4, and soluble epoxide hydrolase (sEH) were detected. Reactive oxygen species (ROS) and epoxyeicosatrienoic acid (EET) levels in mesenteric arteries were also measured.
    KEY FINDINGS: In cirrhotic rats, sitagliptin significantly reduced portal blood flow and portal pressure without effects on systemic pressure and reversed the decreased response of mesenteric arterioles to NE in an endothelium-dependent manner. Sitagliptin suppressed the increased Nox4 expression and ROS production. In vitro studies showed that Nox4 inhibitor enhanced arteriolar response to NE and reduced hydrogen peroxide (H2O2) level in cirrhotic rats. Sitagliptin also reduced EET levels and increased sEH expression of mesenteric vessels. Pre-incubation with sEH inhibitor in vitro reversed sitagliptin-induced augmentation of response to NE in cirrhotic rats.
    SIGNIFICANCE: DPP4 inhibition by sitagliptin in vivo has beneficial effects on portal hypertension in cirrhotic rats through normalizing arterial hypocontractility. DDP4 inhibitor may be a novel strategy in the treatment of patients with cirrhosis and portal hypertension.
    Keywords:  Arterial hypocontractility; DPP4; Liver cirrhosis; Nox4; Portal hypertension; sEH
    DOI:  https://doi.org/10.1016/j.lfs.2021.119895
  7. Antioxidants (Basel). 2021 Jul 26. pii: 1190. [Epub ahead of print]10(8):
    Left Ventricular SGLT1 Protein Expression Correlates with the Extent of Myocardial Nitro-Oxidative Stress in Rats with Pressure and Volume Overload-Induced Heart Failure.
    Alex Ali Sayour, Mihály Ruppert, Attila Oláh, Kálmán Benke, Bálint András Barta, Eszter Zsáry, Haoran Ke, Eszter Mária Horváth, Béla Merkely, Tamás Radovits.
      Myocardial sodium-glucose cotransporter 1 (SGLT1) has been shown to be upregulated in humans with heart failure (HF) with or without diabetes. In vitro studies have linked SGLT1 to increased nitro-oxidative stress in cardiomyocytes. We aimed to assess the relation between left ventricular (LV) SGLT1 expression and the extent of nitro-oxidative stress in two non-diabetic rat models of chronic heart failure (HF) evoked by either pressure (TAC, n = 12) or volume overload (ACF, n = 12). Sham-operated animals (Sham-T and Sham-A, both n = 12) served as controls. Both TAC and ACF induced characteristic LV structural and functional remodeling. Western blotting revealed that LV SGLT1 protein expression was significantly upregulated in both HF models (both p < 0.01), whereas the phosphorylation of ERK1/2 was decreased only in ACF; AMPKα activity was significantly reduced in both models. The protein expression of the Nox4 NADPH oxidase isoform was increased in both TAC and ACF compared with respective controls (both p < 0.01), showing a strong positive correlation with SGLT1 expression (r = 0.855, p < 0.001; and r = 0.798, p = 0.001, respectively). Furthermore, SGLT1 protein expression positively correlated with the extent of myocardial nitro-oxidative stress in failing hearts assessed by 3-nitrotyrosin (r = 0.818, p = 0.006) and 4-hydroxy-2-nonenal (r = 0.733, p = 0.020) immunostaining. Therefore, LV SGLT1 protein expression was upregulated irrespective of the nature of chronic hemodynamic overload, and correlated significantly with the expression of Nox4 and with the level of myocardial nitro-oxidative stress, suggesting a pathophysiological role of SGLT1 in HF.
    Keywords:  NADPH oxidase 4; heart failure; myocardial nitro-oxidative stress; pressure overload; sodium-glucose cotransporter 1; sodium-glucose cotransporter 2 inhibitor; volume overload
    DOI:  https://doi.org/10.3390/antiox10081190
  8. Neural Plast. 2021 ;2021 9928232
    Role of NADPH Oxidase-Induced Hypoxia-Induced Factor-1α Increase in Blood-Brain Barrier Disruption after 2-Hour Focal Ischemic Stroke in Rat.
    Yanping Wang, Yufei Shen, Xin Yu, Jingxia Gu, Xiaoling Zhang, Beiqun Zhou, Yanyun Sun, Congying Xu, Shuxia Qian.
      We recently showed that inhibition of hypoxia-induced factor-1α (HIF-1α) decreased acute ischemic stroke-induced blood-brain barrier (BBB) damage. However, factors that induce the upregulation of HIF-1α expression remain unclear. Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase played a critical role in reperfusion-induced BBB damage after stroke. However, the role of NADPH oxidase in BBB injury during the acute ischemia stage remains unclear. This study is aimed at investigating the role of NADPH oxidase in BBB injury and the expression of HIF-1α after acute ischemic stroke. A sutured middle cerebral artery occlusion (MCAO) model was used to mimic ischemic stroke in rats. Our results show that the inhibition of NADPH oxidase by apocynin can significantly reduce the BBB damage caused by 2 h ischemic stroke accompanied by reducing the degradation of tight junction protein occludin. In addition, treatment with apocynin significantly decreased the upregulation of HIF-1α induced by 2 h MCAO. More importantly, apocynin could also inhibit the MMP-2 upregulation. Of note, HIF-1α was not colocalized with a bigger blood vessel. Taken together, our results showed that inhibition of NADPH oxidase-mediated HIF-1α upregulation reduced BBB damage accompanied by downregulating MMP-2 expression and occludin degradation after 2 h ischemia stroke. These results explored the mechanism of BBB damage after acute ischemic stroke and may help reduce the associated cerebral hemorrhage transformation after thrombolysis and endovascular treatment after ischemic stroke.
    DOI:  https://doi.org/10.1155/2021/9928232
  9. Antioxid Redox Signal. 2021 Aug 26.
    Role of Nox4 in high calcium-induced renal oxidative stress damage and crystal deposition.
    Yang Xun, Peng Zhou, Yuanyuan Yang, Cong Li, Jiaqiao Zhang, Henglong Hu, Baolong Qin, Zongbiao Zhang, Qing Wang, Yuchao Lu, Shaogang Wang.
       AIMS: We aimed to explore the role of nicotinamide adenine dinucleotide phosphate oxidase subunit 4 (Nox4) in the regulation of hypercalciuria-induced renal oxidative damage and crystal depositions.
    RESULTS: High calcium activated Nox4 expression through PKC. Downregulation of Nox4 expression attenuated hypercalciuria-induced osteoblast-associated protein expression, oxidative stress injury and crystal deposition in rat kidneys of 1,25-Dihydroxyvitamin D3 (VitD) urolithiasis model. Furthermore, calcium-induced activation of mitogen-activated protein kinase (MAPK), overexpression of osteoblast-associated protein, oxidative stress injury, apoptosis and calcium salt deposition in normal rat kidney epithelial-like (NRK-52E) cells were reversed by down-regulating Nox4 expression but were enhanced by up-regulating Nox4 expression in vitro. Moreover, calcium-induced increases of osteoblast-associated protein expression were attenuated by the c-Jun-N-terminal kinase (JNK) and extracellular signal-regulated kinase (ERK) inhibitors.
    INNOVATION: Our results demonstrated the effect of Nox4 in the pathological process of kidney stones in in vitro and in vivo studies for the first time. Calcium aggravates renal oxidative stress injury and crystal deposition by activating the Nox4-related reactive oxygen species (ROS)-ERK/JNK pathway in the rat kidney. This study is expected to provide new theoretical basis for the prevention and treatment of kidney stones.
    CONCLUSION: Nox4-derived ROS induced by calcium through PKC caused oxidative stress damage and apoptosis in renal tubular epithelial cells; in addition, Nox4-derived ROS induced by calcium mediated abnormal activation of the bone morphogenetic protein 2 (BMP2) signalling pathway through the MAPK signalling pathway, which induced renal tubular epithelial cells to transdifferentiate into osteoblast-like cells, resulting in the formation of a kidney stone.
    DOI:  https://doi.org/10.1089/ars.2020.8159
This page is being maintained by Thomas Krichel. It was last updated on 2024‒11‒22 at 4:25.