Publications by authors named "Santiago Lamas"

99 Publications

The program of renal fibrogenesis is controlled by microRNAs regulating oxidative metabolism.

Redox Biol 2021 Apr 28;40:101851. Epub 2020 Dec 28.

Program of Physiological and Pathological Processes, Centro de Biología Molecular "Severo Ochoa" (CSIC-UAM), 28049, Madrid, Spain. Electronic address:

Excessive accumulation of extracellular matrix (ECM) is the hallmark of fibrotic diseases. In the kidney, it is the final common pathway of prevalent diseases, leading to chronic renal failure. While cytokines such as TGF-β play a fundamental role in myofibroblast transformation, recent work has shown that mitochondrial dysfunction and defective fatty acid oxidation (FAO), which compromise the main source of energy for renal tubular epithelial cells, have been proposed to be fundamental contributors to the development and progression of kidney fibrosis. MicroRNAs (miRNAs), which regulate gene expression post-transcriptionally, have been reported to control renal fibrogenesis. To identify miRNAs involved in the metabolic derangement of renal fibrosis, we performed a miRNA array screen in the mouse model of unilateral ureteral obstruction (UUO). MiR-150-5p and miR-495-3p were selected for their link to human pathology, their role in mitochondrial metabolism and their targeting of the fatty acid shuttling enzyme CPT1A. We found a 2- and 4-fold upregulation of miR-150-5p and miR-495-5p, respectively, in both the UUO and the folic acid induced nephropathy (FAN) models, while TGF-β1 upregulated their expressions in the human renal tubular epithelial cell line HKC-8. These miRNAs synergized with TGF-β regarding its pro-fibrotic effect by enhancing the fibrosis-associated markers Acta2, Col1α1 and Fn1. Bioenergetics studies showed a reduction of FAO-associated oxygen consumption rate (OCR) in HKC-8 cells in the presence of both miRNAs. Consistently, expression levels of their mitochondrial-related target genes CPT1A, PGC1α and the mitochondrial transcription factor A (TFAM), were reduced by half in renal epithelial cells exposed to these miRNAs. By contrast, we did not detect changes in mitochondrial mass and transmembrane potential (ΔѰm) or mitochondrial superoxide radical anion production. Our data support that miR-150 and miR-495 may contribute to renal fibrogenesis by aggravating the metabolic failure critically involved in tubular epithelial cells, ultimately leading to fibrosis.
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http://dx.doi.org/10.1016/j.redox.2020.101851DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7815809PMC
April 2021

Renal tubule Cpt1a overexpression protects from kidney fibrosis by restoring mitochondrial homeostasis.

J Clin Invest 2021 Mar;131(5)

Program of Physiological and Pathological Processes, Centro de Biología Molecular "Severo Ochoa" (CBMSO) (CSIC-UAM), Madrid, Spain.

Chronic kidney disease (CKD) remains a major epidemiological, clinical, and biomedical challenge. During CKD, renal tubular epithelial cells (TECs) present a persistent inflammatory and profibrotic response. Fatty acid oxidation (FAO), the main source of energy for TECs, is reduced in kidney fibrosis and contributes to its pathogenesis. To determine whether gain of function in FAO (FAO-GOF) could protect from fibrosis, we generated a conditional transgenic mouse model with overexpression of the fatty acid shuttling enzyme carnitine palmitoyl-transferase 1A (CPT1A) in TECs. Cpt1a-knockin (CPT1A-KI) mice subjected to 3 models of renal fibrosis (unilateral ureteral obstruction, folic acid nephropathy [FAN], and adenine-induced nephrotoxicity) exhibited decreased expression of fibrotic markers, a blunted proinflammatory response, and reduced epithelial cell damage and macrophage influx. Protection from fibrosis was also observed when Cpt1a overexpression was induced after FAN. FAO-GOF restored oxidative metabolism and mitochondrial number and enhanced bioenergetics, increasing palmitate oxidation and ATP levels, changes that were also recapitulated in TECs exposed to profibrotic stimuli. Studies in patients showed decreased CPT1 levels and increased accumulation of short- and middle-chain acylcarnitines, reflecting impaired FAO in human CKD. We propose that strategies based on FAO-GOF may constitute powerful alternatives to combat fibrosis inherent to CKD.
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http://dx.doi.org/10.1172/JCI140695DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7919728PMC
March 2021

Deletion of delta-like 1 homologue accelerates renal inflammation by modulating the Th17 immune response.

FASEB J 2021 Jan;35(1):e21213

Cellular and Molecular Biology in Renal and Vascular Pathology, IIS-Fundación Jiménez Díaz. Universidad Autónoma de Madrid, Madrid, Spain.

Preclinical studies have demonstrated that activation of the NOTCH pathway plays a key role in the pathogenesis of kidney damage. There is currently no information on the role of the Delta-like homologue 1 (DLK1), a NOTCH inhibitor, in the regulation of renal damage. Here, we investigated the contribution of DLK1 to experimental renal damage and the underlying molecular mechanisms. Using a Dlk1-null mouse model in the experimental renal damage of unilateral ureteral obstruction, we found activation of NOTCH, as shown by increased nuclear translocation of the NOTCH1 intracellular domain, and upregulation of Dlk2/hey-1 expression compared to wild-type (WT) littermates. NOTCH1 over-activation in Dlk1-null injured kidneys was associated with a higher inflammatory response, characterized by infiltration of inflammatory cells, mainly CD4/IL17A + lymphocytes, and activation of the Th17 immune response. Furthermore, pharmacological NOTCH blockade inhibited the transcription factors controlling Th17 differentiation and gene expression of the Th17 effector cytokine IL-17A and other related-inflammatory factors, linked to a diminution of inflammation in the injured kidneys. We propose that the non-canonical NOTCH ligand DLK1 acts as a NOTCH antagonist in renal injury regulating the Th17-mediated inflammatory response.
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http://dx.doi.org/10.1096/fj.201903131RDOI Listing
January 2021

Role of non-coding-RNAs in response to environmental stressors and consequences on human health.

Redox Biol 2020 10 18;37:101580. Epub 2020 Jul 18.

Pittsburgh Heart, Lung, Blood, and Vascular Medicine Institute, University of Pittsburgh, PA, USA. Electronic address:

Environmental risk factors, including physicochemical agents, noise and mental stress, have a considerable impact on human health. This environmental exposure may lead to epigenetic reprogramming, including changes in non-coding RNAs (ncRNAs) signatures, which can contribute to the pathophysiology state. Oxidative stress is one of the results of this environmental disturbance by modifying cellular processes such as apoptosis, signal transduction cascades, and DNA repair mechanisms. In this review, we delineate environmental risk factors and their influence on (ncRNAs) in connection to disease. We focus on well-studied miRNAs and analyze the novel roles of long-non-coding-RNAs (lncRNAs). We discuss commonly regulated lncRNAs after exposure to different stressors, such as UV, heavy metals and pesticides among others, and the potential role of these lncRNA as exposure biomarkers, epigenetic regulators and potential therapeutic targets to diminish the deleterious secondary response to environmental agents.
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http://dx.doi.org/10.1016/j.redox.2020.101580DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7767735PMC
October 2020

The pHLIP system as a vehicle for microRNAs in the kidney.

Nefrologia 2020 Sep - Oct;40(5):491-498. Epub 2020 Jul 18.

Programa de Procesos Fisiológicos y Patológicos, Centro de Biología Molecular Severo Ochoa (CSIC-UAM), Madrid, España.

MicroRNAs (miRNAs) are small endogenous RNAs that regulate gene expression through post-transcriptional repression of their target messenger RNAs. A study of changes in expression of certain miRNAs in the kidney has supplied evidence on their pathogenic role and therapeutic potential in nephrology. This review proposes a nanotechnology approach based on the binding of analogs or inhibitors of miRNAs formed by peptide nucleic acids (PNAs) to peptides with a transmembrane structure sensitive to a low pH, called pHLIPs (pH [low] insertion peptides). The review draws on the concept that an acidic pH in the microenvironment of the renal tubule may facilitate concentration and distribution of the pHLIP-PNA complex in this organ. In this context, we have demonstrated for the first time that targeted administration of miR-33 inhibitors with the pHLIP system effectively prevents the development of renal fibrosis, thus opening up this technology to new strategies for diagnosis and treatment of kidney diseases.
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http://dx.doi.org/10.1016/j.nefro.2020.05.007DOI Listing
July 2020

Data-dependent normalization strategies for untargeted metabolomics-a case study.

Anal Bioanal Chem 2020 Sep 14;412(24):6391-6405. Epub 2020 Apr 14.

Centro de Metabolómica y Bioanálisis (CEMBIO), Facultad de Farmacia, Universidad San Pablo-CEU, CEU Universities, Urbanización Montepríncipe, 28660, Boadilla del Monte, Madrid, Spain.

Despite the recent advances in the standardization of untargeted metabolomics workflows, there is still a lack of attention to specific data treatment strategies that require deep knowledge of the biological problem and need to be applied after a well-thought out process to understand the effect of the practice. One of those strategies is data normalization. Data-driven assumptions are critical especially addressing unwanted variation present in the biological model as it can be the case in heterogeneous tissues, cells with different sizes or biofluids with different concentrations. Chronic kidney disease (CKD) is a widespread disorder affecting kidney structure and function. Animal models are being developed to be able to get valuable insights into the etiopathogenesis of the condition and effect of the treatments. Moreover, diagnosis and disease staging still require defining appropriate biomarkers. Untargeted metabolomics has the potential to deal with those challenges. Renal fibrosis is one of the consequences of kidney injury which greatly affects the concentration of metabolites in the same quantity of sample. To overcome this challenge, several data normalization strategies have been applied, following a multilevel normalization method with the overall aim of focussing on the relevant biological information and reducing the influence of disturbing factors. A comprehensive evaluation of the performance of the normalization strategies, both on methods assessing the intragroup variation and on the impact on differential analysis, is provided. Finally, we present evidence of the importance of biological-model-driven guided normalization methods and discuss multiple criteria that need to be taken into consideration to obtain robust and reliable data. Special concern is transmitted on the misleading conclusions that might be the consequence of inappropriate data pre-treatment solutions applied for untargeted methods. Graphical abstract.
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http://dx.doi.org/10.1007/s00216-020-02594-9DOI Listing
September 2020

Targeting the progression of chronic kidney disease.

Nat Rev Nephrol 2020 05 14;16(5):269-288. Epub 2020 Feb 14.

Cellular and Molecular Biology in Renal and Vascular Pathology Laboratory, IIS-Fundación Jiménez Díaz-Universidad Autónoma Madrid, Madrid, Spain.

Chronic kidney disease (CKD) is a devastating condition that is reaching epidemic levels owing to the increasing prevalence of diabetes mellitus, hypertension and obesity, as well as ageing of the population. Regardless of the underlying aetiology, CKD is slowly progressive and leads to irreversible nephron loss, end-stage renal disease and/or premature death. Factors that contribute to CKD progression include parenchymal cell loss, chronic inflammation, fibrosis and reduced regenerative capacity of the kidney. Current therapies have limited effectiveness and only delay disease progression, underscoring the need to develop novel therapeutic approaches to either stop or reverse progression. Preclinical studies have identified several approaches that reduce fibrosis in experimental models, including targeting cytokines, transcription factors, developmental and signalling pathways and epigenetic modulators, particularly microRNAs. Some of these nephroprotective strategies are now being tested in clinical trials. Lessons learned from the failure of clinical studies of transforming growth factor β1 (TGFβ1) blockade underscore the need for alternative approaches to CKD therapy, as strategies that target a single pathogenic process may result in unexpected negative effects on simultaneously occurring processes. Additional promising avenues include preventing tubular cell injury and anti-fibrotic therapies that target activated myofibroblasts, the main collagen-producing cells.
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http://dx.doi.org/10.1038/s41581-019-0248-yDOI Listing
May 2020

MiR-9-5p protects from kidney fibrosis by metabolic reprogramming.

FASEB J 2020 01 22;34(1):410-431. Epub 2019 Nov 22.

Department of Cell Biology and Immunology, Centro de Biología Molecular "Severo Ochoa" (CSIC-UAM), Madrid, Spain.

MicroRNAs (miRNAs) regulate gene expression posttranscriptionally and control biological processes (BPs), including fibrogenesis. Kidney fibrosis remains a clinical challenge and miRNAs may represent a valid therapeutic avenue. We show that miR-9-5p protected from renal fibrosis in the mouse model of unilateral ureteral obstruction (UUO). This was reflected in reduced expression of pro-fibrotic markers, decreased number of infiltrating monocytes/macrophages, and diminished tubular epithelial cell injury and transforming growth factor-beta 1 (TGF-β1)-dependent de-differentiation in human kidney proximal tubular (HKC-8) cells. RNA-sequencing (RNA-Seq) studies in the UUO model revealed that treatment with miR-9-5p prevented the downregulation of genes related to key metabolic pathways, including mitochondrial function, oxidative phosphorylation (OXPHOS), fatty acid oxidation (FAO), and glycolysis. Studies in human tubular epithelial cells demonstrated that miR-9-5p impeded TGF-β1-induced bioenergetics derangement. The expression of the FAO-related axis peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1α)-peroxisome proliferator-activated receptor alpha (PPARα) was reduced by UUO, although preserved by the administration of miR-9-5p. We found that in mice null for the mitochondrial master regulator PGC-1α, miR-9-5p was unable to promote a protective effect in the UUO model. We propose that miR-9-5p elicits a protective response to chronic kidney injury and renal fibrosis by inducing reprogramming of the metabolic derangement and mitochondrial dysfunction affecting tubular epithelial cells.
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http://dx.doi.org/10.1096/fj.201901599RRDOI Listing
January 2020

Genetic deficiency or pharmacological inhibition of miR-33 protects from kidney fibrosis.

JCI Insight 2019 11 14;4(22). Epub 2019 Nov 14.

Department of Cell Biology and Immunology, Centro de Biología Molecular "Severo Ochoa," Madrid, Spain.

Previous work has reported the important links between cellular bioenergetics and the development of chronic kidney disease, highlighting the potential for targeting metabolic functions to regulate disease progression. More recently, it has been shown that alterations in fatty acid oxidation (FAO) can have an important impact on the progression of kidney disease. In this work, we demonstrate that loss of miR-33, an important regulator of lipid metabolism, can partially prevent the repression of FAO in fibrotic kidneys and reduce lipid accumulation. These changes were associated with a dramatic reduction in the extent of fibrosis induced in 2 mouse models of kidney disease. These effects were not related to changes in circulating leukocytes because bone marrow transplants from miR-33-deficient animals did not have a similar impact on disease progression. Most important, targeted delivery of miR-33 peptide nucleic acid inhibitors to the kidney and other acidic microenvironments was accomplished using pH low insertion peptides as a carrier. This was effective at both increasing the expression of factors involved in FAO and reducing the development of fibrosis. Together, these findings suggest that miR-33 may be an attractive therapeutic target for the treatment of chronic kidney disease.
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http://dx.doi.org/10.1172/jci.insight.131102DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6948871PMC
November 2019

Deletion of delta-like 1 homologue accelerates fibroblast-myofibroblast differentiation and induces myocardial fibrosis.

Eur Heart J 2019 03;40(12):967-978

Department of Medicine, Cardiovascular Research Institute.

Aims: Myocardial fibrosis is associated with profound changes in ventricular architecture and geometry, resulting in diminished cardiac function. There is currently no information on the role of the delta-like homologue 1 (Dlk1) in the regulation of the fibrotic response. Here, we investigated whether Dlk1 is involved in cardiac fibroblast-to-myofibroblast differentiation and regulates myocardial fibrosis and explored the molecular mechanism underpinning its effects in this process.

Methods And Results: Using Dlk1-knockout mice and adenoviral gene delivery, we demonstrate that overexpression of Dlk1 in cardio-fibroblasts resulted in inhibition of fibroblast proliferation and differentiation into myofibroblasts. This process is mediated by TGF-β1 signalling, since isolated fibroblasts lacking Dlk1 exhibited a higher activation of the TGF-β1/Smad-3 pathway at baseline, leading to an earlier acquisition of a myofibroblast phenotype. Likewise, Dlk1-null mice displayed increased TGF-β1/Smad3 cardiac activity, resulting in infiltration/accumulation of myofibroblasts, induction and deposition of extra-domain A-fibronectin isoform and collagen, and activation of pro-fibrotic markers. Furthermore, these profibrotic events were associated with disrupted myofibril integrity, myocyte hypertrophy, and cardiac dysfunction. Interestingly, Dlk1 expression was down-regulated in ischaemic human and porcine heart tissues. Mechanistically, miR-370 mediated Dlk1's regulation of cardiac fibroblast-myofibroblast differentiation by directly targeting TGFβ-R2/Smad-3 signalling, while the Dlk1 canonical target, Notch pathway, does not seem to play a role in this process.

Conclusion: These findings are the first to demonstrate an inhibitory role of Dlk1 of cardiac fibroblast-to-myofibroblast differentiation by interfering with TGFβ/Smad-3 signalling in the myocardium. Given the deleterious effects of continuous activation of this pathway, we propose Dlk1 as a new potential candidate for therapy in cases where aberrant TGFβ signalling leads to chronic fibrosis.
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http://dx.doi.org/10.1093/eurheartj/ehy188DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6427089PMC
March 2019

Role of glutathione biosynthesis in endothelial dysfunction and fibrosis.

Redox Biol 2018 04 1;14:88-99. Epub 2017 Sep 1.

Department of Cell Biology and Immunology, Centro de Biología Molecular "Severo Ochoa", (CSIC-UAM), Madrid, Spain. Electronic address:

Glutathione (GSH) biosynthesis is essential for cellular redox homeostasis and antioxidant defense. The rate-limiting step requires glutamate-cysteine ligase (GCL), which is composed of the catalytic (GCLc) and the modulatory (GCLm) subunits. To evaluate the contribution of GCLc to endothelial function we generated an endothelial-specific Gclc haplo-insufficient mouse model (Gclc e/+ mice). In murine lung endothelial cells (MLEC) derived from these mice we observed a 50% reduction in GCLc levels compared to lung fibroblasts from the same mice. MLEC obtained from haplo-insufficient mice showed significant reduction in GSH levels as well as increased basal and stimulated ROS levels, reduced phosphorylation of eNOS (Ser 1177) and increased eNOS S-glutathionylation, compared to MLEC from wild type (WT) mice. Studies in mesenteric arteries demonstrated impaired endothelium-dependent vasodilation in Gclc(e/+) male mice, which was corrected by pre-incubation with GSH-ethyl-ester and BH. To study the contribution of endothelial GSH synthesis to renal fibrosis we employed the unilateral ureteral obstruction model in WT and Gclc(e/+) mice. We observed that obstructed kidneys from Gclc(e/+) mice exhibited increased deposition of fibrotic markers and reduced Nrf2 levels. We conclude that the preservation of endothelial GSH biosynthesis is not only critical for endothelial function but also in anti-fibrotic responses.
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http://dx.doi.org/10.1016/j.redox.2017.08.019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5596265PMC
April 2018

European contribution to the study of ROS: A summary of the findings and prospects for the future from the COST action BM1203 (EU-ROS).

Authors:
Javier Egea Isabel Fabregat Yves M Frapart Pietro Ghezzi Agnes Görlach Thomas Kietzmann Kateryna Kubaichuk Ulla G Knaus Manuela G Lopez Gloria Olaso-Gonzalez Andreas Petry Rainer Schulz Jose Vina Paul Winyard Kahina Abbas Opeyemi S Ademowo Catarina B Afonso Ioanna Andreadou Haike Antelmann Fernando Antunes Mutay Aslan Markus M Bachschmid Rui M Barbosa Vsevolod Belousov Carsten Berndt David Bernlohr Esther Bertrán Alberto Bindoli Serge P Bottari Paula M Brito Guia Carrara Ana I Casas Afroditi Chatzi Niki Chondrogianni Marcus Conrad Marcus S Cooke João G Costa Antonio Cuadrado Pham My-Chan Dang Barbara De Smet Bilge Debelec-Butuner Irundika H K Dias Joe Dan Dunn Amanda J Edson Mariam El Assar Jamel El-Benna Péter Ferdinandy Ana S Fernandes Kari E Fladmark Ulrich Förstermann Rashid Giniatullin Zoltán Giricz Anikó Görbe Helen Griffiths Vaclav Hampl Alina Hanf Jan Herget Pablo Hernansanz-Agustín Melanie Hillion Jingjing Huang Serap Ilikay Pidder Jansen-Dürr Vincent Jaquet Jaap A Joles Balaraman Kalyanaraman Danylo Kaminskyy Mahsa Karbaschi Marina Kleanthous Lars-Oliver Klotz Bato Korac Kemal Sami Korkmaz Rafal Koziel Damir Kračun Karl-Heinz Krause Vladimír Křen Thomas Krieg João Laranjinha Antigone Lazou Huige Li Antonio Martínez-Ruiz Reiko Matsui Gethin J McBean Stuart P Meredith Joris Messens Verónica Miguel Yuliya Mikhed Irina Milisav Lidija Milković Antonio Miranda-Vizuete Miloš Mojović María Monsalve Pierre-Alexis Mouthuy John Mulvey Thomas Münzel Vladimir Muzykantov Isabel T N Nguyen Matthias Oelze Nuno G Oliveira Carlos M Palmeira Nikoletta Papaevgeniou Aleksandra Pavićević Brandán Pedre Fabienne Peyrot Marios Phylactides Gratiela G Pircalabioru Andrew R Pitt Henrik E Poulsen Ignacio Prieto Maria Pia Rigobello Natalia Robledinos-Antón Leocadio Rodríguez-Mañas Anabela P Rolo Francis Rousset Tatjana Ruskovska Nuno Saraiva Shlomo Sasson Katrin Schröder Khrystyna Semen Tamara Seredenina Anastasia Shakirzyanova Geoffrey L Smith Thierry Soldati Bebiana C Sousa Corinne M Spickett Ana Stancic Marie José Stasia Holger Steinbrenner Višnja Stepanić Sebastian Steven Kostas Tokatlidis Erkan Tuncay Belma Turan Fulvio Ursini Jan Vacek Olga Vajnerova Kateřina Valentová Frank Van Breusegem Lokman Varisli Elizabeth A Veal A Suha Yalçın Olha Yelisyeyeva Neven Žarković Martina Zatloukalová Jacek Zielonka Rhian M Touyz Andreas Papapetropoulos Tilman Grune Santiago Lamas Harald H H W Schmidt Fabio Di Lisa Andreas Daiber

Redox Biol 2017 10 18;13:94-162. Epub 2017 May 18.

Molecular Cardiology, Center for Cardiology, Cardiology 1, University Medical Center Mainz, Mainz, Germany; DZHK (German Centre for Cardiovascular Research), partner site Rhine-Main, Mainz, Germany. Electronic address:

The European Cooperation in Science and Technology (COST) provides an ideal framework to establish multi-disciplinary research networks. COST Action BM1203 (EU-ROS) represents a consortium of researchers from different disciplines who are dedicated to providing new insights and tools for better understanding redox biology and medicine and, in the long run, to finding new therapeutic strategies to target dysregulated redox processes in various diseases. This report highlights the major achievements of EU-ROS as well as research updates and new perspectives arising from its members. The EU-ROS consortium comprised more than 140 active members who worked together for four years on the topics briefly described below. The formation of reactive oxygen and nitrogen species (RONS) is an established hallmark of our aerobic environment and metabolism but RONS also act as messengers via redox regulation of essential cellular processes. The fact that many diseases have been found to be associated with oxidative stress established the theory of oxidative stress as a trigger of diseases that can be corrected by antioxidant therapy. However, while experimental studies support this thesis, clinical studies still generate controversial results, due to complex pathophysiology of oxidative stress in humans. For future improvement of antioxidant therapy and better understanding of redox-associated disease progression detailed knowledge on the sources and targets of RONS formation and discrimination of their detrimental or beneficial roles is required. In order to advance this important area of biology and medicine, highly synergistic approaches combining a variety of diverse and contrasting disciplines are needed.
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http://dx.doi.org/10.1016/j.redox.2017.05.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5458069PMC
October 2017

The Role of MicroRNAs in Environmental Risk Factors, Noise-Induced Hearing Loss, and Mental Stress.

Antioxid Redox Signal 2018 03 30;28(9):773-796. Epub 2017 Jun 30.

1 Department of Cell Biology and Immunology, Centro de Biología Molecular "Severo Ochoa" (CSIC-UAM) , Madrid, Spain .

Significance: MicroRNAs (miRNAs) are important regulators of gene expression and define part of the epigenetic signature. Their influence on every realm of biomedicine is established and progressively increasing. The impact of environment on human health is enormous. Among environmental risk factors impinging on quality of life are those of chemical nature (toxic chemicals, heavy metals, pollutants, and pesticides) as well as those related to everyday life such as exposure to noise or mental and psychosocial stress. Recent Advances: This review elaborates on the relationship between miRNAs and these environmental risk factors.

Critical Issues: The most relevant facts underlying the role of miRNAs in the response to these environmental stressors, including redox regulatory changes and oxidative stress, are highlighted and discussed. In the cases wherein miRNA mutations are relevant for this response, the pertinent literature is also reviewed.

Future Directions: We conclude that, even though in some cases important advances have been made regarding close correlations between specific miRNAs and biological responses to environmental risk factors, a need for prospective large-cohort studies is likely necessary to establish causative roles. Antioxid. Redox Signal. 28, 773-796.
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http://dx.doi.org/10.1089/ars.2017.7175DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5911706PMC
March 2018

Introduction to Special Issue "Redox regulation of cardiovascular signaling in health and disease".

Free Radic Biol Med 2017 08 24;109:1-3. Epub 2017 Apr 24.

Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.

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http://dx.doi.org/10.1016/j.freeradbiomed.2017.04.030DOI Listing
August 2017

Protective role for miR-9-5p in the fibrogenic transformation of human dermal fibroblasts.

Fibrogenesis Tissue Repair 2016 10;9. Epub 2016 May 10.

Department of Cell Biology and Immunology, Centro de Biología Molecular "Severo Ochoa", Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid, Nicolás Cabrera 1, 28049 Madrid, Spain.

Background: Excessive accumulation of extracellular matrix (ECM) proteins is the hallmark of fibrotic diseases, including skin fibrosis. This response relies on the activation of dermal fibroblasts that evolve into a pro-fibrogenic phenotype. One of the major players in this process is the cytokine transforming growth factor-β (TGF-β). MicroRNAs (miRNAs) are small non-coding RNAs that post-transcriptionally regulate gene expression affecting a wide range of pathophysiological events including fibrogenesis. MicroRNA-9-5p (miR-9-5p) has been shown to exert a protective role in lung and peritoneal fibrosis. This study aimed to evaluate the role of miR-9-5p in skin fibrosis.

Results: miR-9-5p is up-regulated in TGF-β1-treated human dermal fibroblasts (HDFs). In silico identification of miR-9-5p targets spotted the type II TGF-β receptor (TGFBR2) as a potential TGF-β signaling-related effector for this miRNA. Consistently, over-expression of miR-9-5p in HDFs down-regulated TGFBR2 at both the mRNA and protein levels and reduced the phosphorylation of Smad2 and the translocation of Smad2/3 to the nucleus. In keeping, over-expression of miR-9-5p significantly delayed TGF-β1-dependent transformation of dermal fibroblasts, decreasing the expression of ECM protein collagen, type I, alpha 1 (Col1α1), and fibronectin (FN), the amount of secreted collagen proteins, and the expression of the archetypal myofibroblast marker alpha-smooth muscle actin (α-SMA). By contrast, specific inhibition of miR-9-5p resulted in enhanced presence of fibrosis markers. The expression of miR-9-5p was also detected in the skin and plasma in the mouse model of bleomycin-induced dermal fibrosis. Using lentiviral constructs, we demonstrated that miR-9-5p over-expression was also capable of deterring fibrogenesis in this same model.

Conclusions: miR-9-5p significantly prevents fibrogenesis in skin fibrosis. This is mediated by an abrogation of TGF-β-mediated signaling through the down-regulation of TGFBR2 expression in HDFs. These results may pave the way for future diagnostic or therapeutic developments for skin fibrosis based on miR-9-5p.
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http://dx.doi.org/10.1186/s13069-016-0044-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4891847PMC
June 2016

Targeting vascular (endothelial) dysfunction.

Br J Pharmacol 2017 06 4;174(12):1591-1619. Epub 2016 Jul 4.

Center of Cardiology, Medical Center of the Johannes Gutenberg University, Mainz, Germany.

Cardiovascular diseases are major contributors to global deaths and disability-adjusted life years, with hypertension a significant risk factor for all causes of death. The endothelium that lines the inner wall of the vasculature regulates essential haemostatic functions, such as vascular tone, circulation of blood cells, inflammation and platelet activity. Endothelial dysfunction is an early predictor of atherosclerosis and future cardiovascular events. We review the prognostic value of obtaining measurements of endothelial function, the clinical techniques for its determination, the mechanisms leading to endothelial dysfunction and the therapeutic treatment of endothelial dysfunction. Since vascular oxidative stress and inflammation are major determinants of endothelial function, we have also addressed current antioxidant and anti-inflammatory therapies. In the light of recent data that dispute the prognostic value of endothelial function in healthy human cohorts, we also discuss alternative diagnostic parameters such as vascular stiffness index and intima/media thickness ratio. We also suggest that assessing vascular function, including that of smooth muscle and even perivascular adipose tissue, may be an appropriate parameter for clinical investigations.

Linked Articles: This article is part of a themed section on Redox Biology and Oxidative Stress in Health and Disease. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.12/issuetoc.
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http://dx.doi.org/10.1111/bph.13517DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5446575PMC
June 2017

MicroRNA-mediated regulation of glutathione and methionine metabolism and its relevance for liver disease.

Free Radic Biol Med 2016 11 24;100:66-72. Epub 2016 Mar 24.

Department of Cell Biology and Immunology, Centro de Biología Molecular "Severo Ochoa" (CSIC-UAM), Nicolás Cabrera 1, 28049 Madrid, Spain. Electronic address:

The discovery of the microRNA (miRNA) family of small RNAs as fundamental regulators of post-transcriptional gene expression has fostered research on their importance in every area of biology and clinical medicine. In the particular area of liver metabolism and disease, miRNAs are gaining increasing importance. By focusing on two fundamental hepatic biosynthetic pathways, glutathione and methionine, we review recent advances on the comprehension of the role of miRNAs in liver pathophysiology and more specifically of models of hepatic cholestasis/fibrosis and hepatocellular carcinoma.
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http://dx.doi.org/10.1016/j.freeradbiomed.2016.03.021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5749629PMC
November 2016

Virtual issue by COST Action BM1203 (EU-ROS) "Emerging concepts in redox biology and oxidative stress".

Redox Biol 2016 08 21;8:439-41. Epub 2015 Dec 21.

Department of Cell Biology and Immunology, Centro de Biología Molecular "Severo Ochoa" (CSIC-UAM), Nicolás Cabrera 1, 28049 Madrid, Spain. Electronic address:

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http://dx.doi.org/10.1016/j.redox.2015.12.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4885012PMC
August 2016

Role of redoximiRs in fibrogenesis.

Redox Biol 2016 Apr 19;7:58-67. Epub 2015 Nov 19.

Department of Cell Biology and Immunology, Centro de Biología Molecular "Severo Ochoa" (CBMSO), Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid, Nicolás Cabrera 1, 28049 Madrid, Spain. Electronic address:

Fibrosis can be defined as an excessive accumulation of extracellular matrix (ECM) components, ultimately leading to stiffness, scarring and devitalized tissue. MicroRNAs (miRNAs) are short, 19-25 nucleotides (nt), non-coding RNAs involved in the post-transcriptional regulation of gene expression. Recently, miRNAs have also emerged as powerful regulators of fibrotic processes and have been termed "fibromiRs". Oxidative stress represents a self-perpetuating mechanism in fibrogenesis. MiRNAs can also influence the expression of genes responsible for the generation of reactive oxygen species (ROS) and antioxidant defence and are termed "redoximiRs". Here, we review the current knowledge of mechanisms by which "redoximiRs" regulate fibrogenesis. This new set of miRNAs may be called "redoxifibromiRs".
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http://dx.doi.org/10.1016/j.redox.2015.11.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4683389PMC
April 2016

NOX4-dependent Hydrogen peroxide promotes shear stress-induced SHP2 sulfenylation and eNOS activation.

Free Radic Biol Med 2015 Dec 30;89:419-30. Epub 2015 Sep 30.

Centro de Biología Molecular "Severo Ochoa" CSIC-UAM, Campus Universidad Autónoma, E-28049 Madrid, Spain. Electronic address:

Laminar shear stress (LSS) triggers signals that ultimately result in atheroprotection and vasodilatation. Early responses are related to the activation of specific signaling cascades. We investigated the participation of redox-mediated modifications and in particular the role of hydrogen peroxide (H2O2) in the sulfenylation of redox-sensitive phosphatases. Exposure of vascular endothelial cells to short periods of LSS (12 dyn/cm(2)) resulted in the generation of superoxide radical anion as detected by the formation of 2-hydroxyethidium by HPLC and its subsequent conversion to H2O2, which was corroborated by the increase in the fluorescence of the specific peroxide sensor HyPer. By using biotinylated dimedone we detected increased total protein sulfenylation in the bovine proteome, which was dependent on NADPH oxidase 4 (NOX4)-mediated generation of peroxide. Mass spectrometry analysis allowed us to identify the phosphatase SHP2 as a protein susceptible to sulfenylation under LSS. Given the dependence of FAK activity on SHP2 function, we explored the role of FAK under LSS conditions. FAK activation and subsequent endothelial NO synthase (eNOS) phosphorylation were promoted by LSS and both processes were dependent on NOX4, as demonstrated in lung endothelial cells isolated from NOX4-null mice. These results support the idea that LSS elicits redox-sensitive signal transduction responses involving NOX4-dependent generation of hydrogen peroxide, SHP2 sulfenylation, and ulterior FAK-mediated eNOS activation.
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http://dx.doi.org/10.1016/j.freeradbiomed.2015.08.014DOI Listing
December 2015

miR-9-5p suppresses pro-fibrogenic transformation of fibroblasts and prevents organ fibrosis by targeting NOX4 and TGFBR2.

EMBO Rep 2015 Oct 27;16(10):1358-77. Epub 2015 Aug 27.

Department of Cell Biology and Immunology, Centro de Biología Molecular "Severo Ochoa" (CBMSO), Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid, Madrid, Spain

Uncontrolled extracellular matrix (ECM) production by fibroblasts in response to injury contributes to fibrotic diseases, including idiopathic pulmonary fibrosis (IPF). Reactive oxygen species (ROS) generation is involved in the pathogenesis of IPF. Transforming growth factor-β1 (TGF-β1) stimulates the production of NADPH oxidase 4 (NOX4)-dependent ROS, promoting lung fibrosis (LF). Dysregulation of microRNAs (miRNAs) has been shown to contribute to LF. To identify miRNAs involved in redox regulation relevant for IPF, we performed arrays in human lung fibroblasts exposed to ROS. miR-9-5p was selected as the best candidate and we demonstrate its inhibitory effect on TGF-β receptor type II (TGFBR2) and NOX4 expression. Increased expression of miR-9-5p abrogates TGF-β1-dependent myofibroblast phenotypic transformation. In the mouse model of bleomycin-induced LF, miR-9-5p dramatically reduces fibrogenesis and inhibition of miR-9-5p and prevents its anti-fibrotic effect both in vitro and in vivo. In lung specimens from patients with IPF, high levels of miR-9-5p are found. In omentum-derived mesothelial cells (MCs) from patients subjected to peritoneal dialysis (PD), miR-9-5p also inhibits mesothelial to myofibroblast transformation. We propose that TGF-β1 induces miR-9-5p expression as a self-limiting homeostatic response.
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http://dx.doi.org/10.15252/embr.201540750DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4766462PMC
October 2015

Antioxidant responses and cellular adjustments to oxidative stress.

Redox Biol 2015 Dec 21;6:183-197. Epub 2015 Jul 21.

Department of Cell Biology and Immunology, Centro de Biología Molecular "Severo Ochoa" (CSIC-UAM), Nicolás Cabrera 1, 28049 Madrid, Spain. Electronic address:

Redox biological reactions are now accepted to bear the Janus faceted feature of promoting both physiological signaling responses and pathophysiological cues. Endogenous antioxidant molecules participate in both scenarios. This review focuses on the role of crucial cellular nucleophiles, such as glutathione, and their capacity to interact with oxidants and to establish networks with other critical enzymes such as peroxiredoxins. We discuss the importance of the Nrf2-Keap1 pathway as an example of a transcriptional antioxidant response and we summarize transcriptional routes related to redox activation. As examples of pathophysiological cellular and tissular settings where antioxidant responses are major players we highlight endoplasmic reticulum stress and ischemia reperfusion. Topologically confined redox-mediated post-translational modifications of thiols are considered important molecular mechanisms mediating many antioxidant responses, whereas redox-sensitive microRNAs have emerged as key players in the posttranscriptional regulation of redox-mediated gene expression. Understanding such mechanisms may provide the basis for antioxidant-based therapeutic interventions in redox-related diseases.
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http://dx.doi.org/10.1016/j.redox.2015.07.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4534574PMC
December 2015

L-Plastin S-glutathionylation promotes reduced binding to β-actin and affects neutrophil functions.

Free Radic Biol Med 2015 Sep 14;86:1-15. Epub 2015 Apr 14.

Pharmacology Division, CSIR-Central Drug Research Institute, Lucknow, India. Electronic address:

Posttranslational modifications (PTMs) of cytoskeleton proteins due to oxidative stress associated with several pathological conditions often lead to alterations in cell function. The current study evaluates the effect of nitric oxide (DETA-NO)-induced oxidative stress-related S-glutathionylation of cytoskeleton proteins in human PMNs. By using in vitro and genetic approaches, we showed that S-glutathionylation of L-plastin (LPL) and β-actin promotes reduced chemotaxis, polarization, bactericidal activity, and phagocytosis. We identified Cys-206, Cys-283, and Cys-460as S-thiolated residues in the β-actin-binding domain of LPL, where cys-460 had the maximum score. Site-directed mutagenesis of LPL Cys-460 further confirmed the role in the redox regulation of LPL. S-Thiolation diminished binding as well as the bundling activity of LPL. The presence of S-thiolated LPL was detected in neutrophils from both diabetic patients and db/db mice with impaired PMN functions. Thus, enhanced nitroxidative stress may results in LPL S-glutathionylation leading to impaired chemotaxis, polarization, and bactericidal activity of human PMNs, providing a mechanistic basis for their impaired functions in diabetes mellitus.
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http://dx.doi.org/10.1016/j.freeradbiomed.2015.04.008DOI Listing
September 2015

Targeting of Gamma-Glutamyl-Cysteine Ligase by miR-433 Reduces Glutathione Biosynthesis and Promotes TGF-β-Dependent Fibrogenesis.

Antioxid Redox Signal 2015 Nov 9;23(14):1092-105. Epub 2015 Jan 9.

1 Departamento de Biología Celular e Inmunología, Centro de Biología Molecular "Severo Ochoa, " Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid , Madrid, Spain .

Aims: Glutathione (GSH) is the main antioxidant against cell damage. Several pathological states course with reduced nucleophilic tone and perturbation of redox homeostasis due to changes in the 2GSH/GSSG ratio. Here, we investigated the regulation of the rate-limiting GSH biosynthetic heterodimeric enzyme γ-glutamyl-cysteine ligase (GCL) by microRNAs (miRNAs).

Results: "In silico" analysis of the 3'- untranslated regions (UTRs) of both catalytic (GCLc) and regulatory (GCLm) subunits of GCL enabled an identification of miR-433 as a strong candidate for the targeting of GCL. Transitory overexpression of miR-433 in human umbilical vein endothelial cells (HUVEC) showed a downregulation of both GCLc and GCLm in a nuclear factor (erythroid-derived 2)-like 2 (Nrf2)-independent manner. Increases in pro-oxidant stimuli such as exposure to hydrogen peroxide or GSH depletion in endothelial and hepatic cells caused an expected increase in GCLc and GCLm protein expression and abrogation of miR-433 levels, thus supporting a cross-regulation of these pathways. Treatment of HUVEC with miR-433 resulted in reduced antioxidant and redox potentials, increased S-glutathionylation, and reduced endothelial nitric oxide synthase activation. In vivo models of renal and hepatic fibrosis were associated with transforming growth factor β1 (TGF-β1)-related reduction of GCLc and GCLm levels that were miR-433 dependent.

Innovation And Conclusion: We describe for the first time an miRNA, miR-433, capable of directly targeting GCL and promoting functional consequences in endothelial physiology and fibrotic processes by decreasing GSH levels.
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http://dx.doi.org/10.1089/ars.2014.6025DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4657521PMC
November 2015

Laminar shear stress regulates mitochondrial dynamics, bioenergetics responses and PRX3 activation in endothelial cells.

Biochim Biophys Acta 2014 Nov 17;1843(11):2403-13. Epub 2014 Jul 17.

Centro de Biología Molecular 'Severo Ochoa' CSIC-UAM, Campus Universidad Autónoma, Nicolás Cabrera 1, E-28049 Madrid, Spain. Electronic address:

Endothelial cells in the vascular system are constantly subjected to the frictional force of shear stress due to the pulsatile nature of blood flow. Although several proteins form part of the shear stress mechano-sensing pathway, the identification of mechano-transducing pathways is largely unknown. Given the increasing evidence for a signaling function of mitochondria in endothelial cells, the aim of this study was to investigate their role as mechano-sensor organelles during laminar shear stress (LSS). We demonstrated that LSS activates intracellular signaling pathways that modulate not only mitochondrial dynamics but also mitochondrial function. At early time points of LSS, the fission-related protein Drp1 was recruited from the cytosol to mitochondria and activated mitochondrial fission. LSS-dependent increase in intracellular Ca(2+) concentration was indispensable for mitochondrial fission. As alterations in mitochondrial dynamics have been related to changes in bioenergetics profiles, we studied mitochondrial function after LSS. We found that LSS decreased respiration rate, increased mitochondrial membrane potential and promoted the mitochondrial generation of ROS with the subsequent oxidation and activation of the antioxidant enzyme PRX3. Our data support a novel and active role for mitochondria in endothelial cells as active players, able to transduce the mechanical force of shear stress in the vascular endothelium into a biological response.
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http://dx.doi.org/10.1016/j.bbamcr.2014.07.003DOI Listing
November 2014

A pathogenetic role for endothelin-1 in peritoneal dialysis-associated fibrosis.

J Am Soc Nephrol 2015 Jan 10;26(1):173-82. Epub 2014 Jul 10.

Centro de Biología Molecular Severo Ochoa, Consejo Superior de Investigaciones Científicas, Universidad Autónoma de Madrid, Madrid, Spain;

In patients undergoing peritoneal dialysis (PD), chronic exposure to nonphysiologic PD fluids elicits low-grade peritoneal inflammation, leading to fibrosis and angiogenesis. Phenotype conversion of mesothelial cells into myofibroblasts, the so-called mesothelial-to-mesenchymal transition (MMT), significantly contributes to the peritoneal dysfunction related to PD. A number of factors have been described to induce MMT in vitro and in vivo, of which TGF-β1 is probably the most important. The vasoconstrictor peptide endothelin-1 (ET-1) is a transcriptional target of TGF-β1 and mediates excessive scarring and fibrosis in several tissues. This work studied the contribution of ET-1 to the development of peritoneal damage and failure in a mouse model of PD. ET-1 and its receptors were expressed in the peritoneal membrane and upregulated on PD fluid exposure. Administration of an ET receptor antagonist, either bosentan or macitentan, markedly attenuated PD-induced MMT, fibrosis, angiogenesis, and peritoneal functional decline. Adenovirus-mediated overexpression of ET-1 induced MMT in human mesothelial cells in vitro and promoted the early cellular events associated with peritoneal dysfunction in vivo. Notably, TGF-β1-blocking peptides prevented these actions of ET-1. Furthermore, a positive reciprocal relationship was observed between ET-1 expression and TGF-β1 expression in human mesothelial cells. These results strongly support a role for an ET-1/TGF-β1 axis as an inducer of MMT and subsequent peritoneal damage and fibrosis, and they highlight ET-1 as a potential therapeutic target in the treatment of PD-associated dysfunction.
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http://dx.doi.org/10.1681/ASN.2013070799DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4279729PMC
January 2015

Acute hypoxia produces a superoxide burst in cells.

Free Radic Biol Med 2014 Jun 15;71:146-156. Epub 2014 Mar 15.

Servicio de Inmunología, Hospital Universitario de La Princesa, Instituto de Investigación Sanitaria Princesa, E-28006 Madrid, Spain. Electronic address:

Oxygen is a key molecule for cell metabolism. Eukaryotic cells sense the reduction in oxygen availability (hypoxia) and trigger a series of cellular and systemic responses to adapt to hypoxia, including the optimization of oxygen consumption. Many of these responses are mediated by a genetic program induced by the hypoxia-inducible transcription factors (HIFs), regulated by a family of prolyl hydroxylases (PHD or EGLN) that use oxygen as a substrate producing HIF hydroxylation. In parallel to these oxygen sensors modulating gene expression within hours, acute modulation of protein function in response to hypoxia is known to occur within minutes. Free radicals acting as second messengers, and oxidative posttranslational modifications, have been implied in both groups of responses. Localization and speciation of the paradoxical increase in reactive oxygen species production in hypoxia remain debatable. We have observed that several cell types respond to acute hypoxia with a transient increase in superoxide production for about 10 min, probably originating in the mitochondria. This may explain in part the apparently divergent results found by various groups that have not taken into account the time frame of hypoxic ROS production. We propose that this acute and transient hypoxia-induced superoxide burst may be translated into oxidative signals contributing to hypoxic adaptation and preconditioning.
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http://dx.doi.org/10.1016/j.freeradbiomed.2014.03.011DOI Listing
June 2014

Hydrogen peroxide signaling in vascular endothelial cells.

Redox Biol 2014 1;2:529-34. Epub 2014 Mar 1.

Centro de Biología Molecular 'Severo Ochoa' CSIC-UAM, Campus Universidad Autónoma, Nicolás Cabrera 1, Madrid E-28049, Spain.

Redox signaling is implicated in different physiological and pathological events in the vasculature. Among the different reactive oxygen species, hydrogen peroxide (H2O2) is a very good candidate to perform functions as an intracellular messenger in the regulation of several biological events. In this review, we summarize the main physiological sources of H2O2 in the endothelium and the molecular mechanisms by which it is able to act as a signaling mediator in the vasculature.
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http://dx.doi.org/10.1016/j.redox.2014.02.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3953958PMC
March 2015