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2. NADPH Oxidase 5 (NOX5) Upregulates MMP-10 Production and Cell Migration in Human Endothelial Cells.

Author

Marqués, Javier, Ainzúa, Elena, Orbe, Josune, Martínez-Azcona, María, Martínez-González, José, and Zalba, Guillermo

Subjects
MATRIX metalloproteinases, NADPH oxidase, CELL migration, ENDOTHELIAL cells, ANGIOTENSIN II
Abstract

NADPH oxidases (NOXs) have been described as critical players in vascular remodeling, a mechanism modulated by matrix metalloproteinases. In this study, we describe for the first time the upregulation of MMP-10 through the activation of NOX5 in endothelial cells. In a chronic NOX5 overexpression model in human endothelial cells, MMP-10 production was measured at different levels: extracellular secretion, gene expression (mRNA and protein levels), and promoter activity. Effects on cell migration were quantified using wound healing assays. NOX5 overexpression increased MMP-10 production, favoring cell migration. In fact, NOX5 and MMP-10 silencing prevented this promigratory effect. We showed that NOX5-mediated MMP-10 upregulation involves the redox-sensitive JNK/AP-1 signaling pathway. All these NOX5-dependent effects were enhanced by angiotensin II (Ang II). Interestingly, MMP-10 protein levels were found to be increased in the hearts of NOX5-expressing mice. In conclusion, we described that NOX5-generated ROS may modulate the MMP-10 expression in endothelial cells, which leads to endothelial cell migration and may play a key role in vascular remodeling. [ABSTRACT FROM AUTHOR]

Published
2024
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3. Vascular NADPH Oxidases and Atherothrombotic Stroke.

Author

Marqués, Javier and Zalba, Guillermo

Subjects
*NADPH oxidase, *OXIDATIVE stress, *REACTIVE oxygen species, *HOMOLOGY (Biology), *INFORMATION retrieval
Abstract

Oxidative stress constitutes a main molecular mechanism underlying cardiovascular diseases (CVDs). This pathological mechanism can be triggered by NADPH oxidases (NOXs), which produce reactive oxygen species (ROS). In fact, the different NOXs have been associated with myocardial infarction, atherothrombosis, and stroke. More specifically, we will focus on the implications of NOXs in atherothrombotic stroke. Each NOX member participates in a different way in the several stages of this disease: endothelial dysfunction, immune cell infiltration, foam cell genesis, vascular smooth muscle cells (VSMC) proliferation, and atherosclerotic plaque formation. Additionally, some NOXs are involved in plaque instability, thrombosis, ischemic stroke, and ischemia-reperfusion injury (IRI). Interestingly, the effects of NOXs in this pathology depend on the specific homolog, the cell type in which they are activated, and the stage of the disease. In this review we summarize the most up-to-date information about the implications of vascular NOXs in each of these processes. Finally, we highlight some limitations and future perspectives on the study of NOXs in CVDs. [ABSTRACT FROM AUTHOR]

Published
2024
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6. NADPH Oxidase 5 (NOX5) Overexpression Promotes Endothelial Dysfunction via Cell Apoptosis, Migration, and Metabolic Alterations in Human Brain Microvascular Endothelial Cells (hCMEC/D3)

Author

Marqués, Javier, primary, Fernández-Irigoyen, Joaquín, additional, Ainzúa, Elena, additional, Martínez-Azcona, María, additional, Cortés, Adriana, additional, Roncal, Carmen, additional, Orbe, Josune, additional, Santamaría, Enrique, additional, and Zalba, Guillermo, additional

Published
2022
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9. Supplemental Data Interferon stimulated gene 15 pathway is a novel mediator of endothelial dysfunction and aneurysms development in Angiotensin II infused mice through increased oxidative stress

Author

González-Amor, María, García-Redondo, Ana B., Jorge, Inmaculada, Zalba, Guillermo, Becares, Martina, Ruiz-Rodríguez, María J., Rodríguez-Sinovas, Cristina, Bermeo, Hugo, Rodrigues-Díez, Raquel, Ríos, Francisco J, Montezano, Augusto C., Martínez-González, José, Vázquez, Jesús, Redondo, Juan Miguel, Touyz, Rhian M., Guerra, Susana, Salaices, Mercedes, Briones, Ana M., González-Amor, María, García-Redondo, Ana B., Jorge, Inmaculada, Zalba, Guillermo, Becares, Martina, Ruiz-Rodríguez, María J., Rodríguez-Sinovas, Cristina, Bermeo, Hugo, Rodrigues-Díez, Raquel, Ríos, Francisco J, Montezano, Augusto C., Martínez-González, José, Vázquez, Jesús, Redondo, Juan Miguel, Touyz, Rhian M., Guerra, Susana, Salaices, Mercedes, and Briones, Ana M.

Published
2022

10. Interferon-stimulated gene 15 pathway is a novel mediator of endothelial dysfunction and aneurysms development in angiotensin II infused mice through increased oxidative stress

Author

European Commission, Ministerio de Economía y Competitividad (España), Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), Ministerio de Educación, Cultura y Deporte (España), Instituto de Salud Carlos III, Comunidad de Madrid, Universidad Autónoma de Madrid, González-Amor, María, García-Redondo, Ana B., Jorge, Inmaculada, Zalba, Guillermo, Becares, Martina, Ruiz-Rodríguez, María J., Rodríguez-Sinovas, Cristina, Bermeo, Hugo, Rodrigues-Díez, Raquel, Ríos, Francisco J, Montezano, Augusto C., Martínez-González, José, Vázquez, Jesús, Redondo, Juan Miguel, Touyz, Rhian M., Guerra, Susana, Salaices, Mercedes, Briones, Ana M., European Commission, Ministerio de Economía y Competitividad (España), Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), Ministerio de Educación, Cultura y Deporte (España), Instituto de Salud Carlos III, Comunidad de Madrid, Universidad Autónoma de Madrid, González-Amor, María, García-Redondo, Ana B., Jorge, Inmaculada, Zalba, Guillermo, Becares, Martina, Ruiz-Rodríguez, María J., Rodríguez-Sinovas, Cristina, Bermeo, Hugo, Rodrigues-Díez, Raquel, Ríos, Francisco J, Montezano, Augusto C., Martínez-González, José, Vázquez, Jesús, Redondo, Juan Miguel, Touyz, Rhian M., Guerra, Susana, Salaices, Mercedes, and Briones, Ana M.

Abstract

AIMS: Interferon-stimulated gene 15 (ISG15) encodes a ubiquitin-like protein that induces a reversible post-translational modification (ISGylation) and can also be secreted as a free form. ISG15 plays an essential role as host-defence response to microbial infection; however, its contribution to vascular damage associated with hypertension is unknown. METHODS AND RESULTS: Bioinformatics identified ISG15 as a mediator of hypertension-associated vascular damage. ISG15 expression positively correlated with systolic and diastolic blood pressure and carotid intima-media thickness in human peripheral blood mononuclear cells. Consistently, Isg15 expression was enhanced in aorta from hypertension models and in angiotensin II (AngII)-treated vascular cells and macrophages. Proteomics revealed differential expression of proteins implicated in cardiovascular function, extracellular matrix and remodelling, and vascular redox state in aorta from AngII-infused ISG15-/- mice. Moreover, ISG15-/- mice were protected against AngII-induced hypertension, vascular stiffness, elastin remodelling, endothelial dysfunction, and expression of inflammatory and oxidative stress markers. Conversely, mice with excessive ISGylation (USP18C61A) show enhanced AngII-induced hypertension, vascular fibrosis, inflammation and reactive oxygen species (ROS) generation along with elastin breaks, aortic dilation, and rupture. Accordingly, human and murine abdominal aortic aneurysms showed augmented ISG15 expression. Mechanistically, ISG15 induces vascular ROS production, while antioxidant treatment prevented ISG15-induced endothelial dysfunction and vascular remodelling. CONCLUSION: ISG15 is a novel mediator of vascular damage in hypertension through oxidative stress and inflammation.

Published
2022

13. Interferon-stimulated gene 15 pathway is a novel mediator of endothelial dysfunction and aneurysms development in angiotensin II infused mice through increased oxidative stress.

Author

González-Amor, María, García-Redondo, Ana B, Jorge, Inmaculada, Zalba, Guillermo, Becares, Martina, Ruiz-Rodríguez, María J, Rodríguez, Cristina, Bermeo, Hugo, Rodrigues-Díez, Raquel, Rios, Francisco J, Montezano, Augusto C, Martínez-González, Jose, Vázquez, Jesús, Redondo, Juan Miguel, Touyz, Rhian M, Guerra, Susana, Salaices, Mercedes, and Briones, Ana M

Subjects
ENDOTHELIUM diseases, ANGIOTENSIN II, OXIDATIVE stress, CAROTID intima-media thickness, MONONUCLEAR leukocytes
Abstract

Aims Interferon-stimulated gene 15 (ISG15) encodes a ubiquitin-like protein that induces a reversible post-translational modification (ISGylation) and can also be secreted as a free form. ISG15 plays an essential role as host-defence response to microbial infection; however, its contribution to vascular damage associated with hypertension is unknown. Methods and results Bioinformatics identified ISG15 as a mediator of hypertension-associated vascular damage. ISG15 expression positively correlated with systolic and diastolic blood pressure and carotid intima-media thickness in human peripheral blood mononuclear cells. Consistently, Isg15 expression was enhanced in aorta from hypertension models and in angiotensin II (AngII)-treated vascular cells and macrophages. Proteomics revealed differential expression of proteins implicated in cardiovascular function, extracellular matrix and remodelling, and vascular redox state in aorta from AngII-infused ISG15–/– mice. Moreover, ISG15–/– mice were protected against AngII-induced hypertension, vascular stiffness, elastin remodelling, endothelial dysfunction, and expression of inflammatory and oxidative stress markers. Conversely, mice with excessive ISGylation (USP18C61A) show enhanced AngII-induced hypertension, vascular fibrosis, inflammation and reactive oxygen species (ROS) generation along with elastin breaks, aortic dilation, and rupture. Accordingly, human and murine abdominal aortic aneurysms showed augmented ISG15 expression. Mechanistically, ISG15 induces vascular ROS production, while antioxidant treatment prevented ISG15-induced endothelial dysfunction and vascular remodelling. Conclusion ISG15 is a novel mediator of vascular damage in hypertension through oxidative stress and inflammation. [ABSTRACT FROM AUTHOR]

Published
2022
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14. Interferon-stimulated gene 15 pathway is a novel mediator of endothelial dysfunction and aneurysms development in angiotensin II infused mice through increased oxidative stress

Author

González-Amor, María, primary, García-Redondo, Ana B, additional, Jorge, Inmaculada, additional, Zalba, Guillermo, additional, Becares, Martina, additional, Ruiz-Rodríguez, María J, additional, Rodríguez, Cristina, additional, Bermeo, Hugo, additional, Rodrigues-Díez, Raquel, additional, Rios, Francisco J, additional, Montezano, Augusto C, additional, Martínez-González, Jose, additional, Vázquez, Jesús, additional, Redondo, Juan Miguel, additional, Touyz, Rhian M, additional, Guerra, Susana, additional, Salaices, Mercedes, additional, and Briones, Ana M, additional

Published
2021
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32. Pistachio consumption modulates DNA oxidation and genes related to telomere maintenance: a crossover randomized clinical trial

Author

Universitat Rovira i Virgili, Canudas, Silvia; Hernandez-Alonso, Pablo; Galie, Serena; Muralidharan, Jananee; Morell-Azanza, Lydia; Zalba, Guillermo; Garcia-Gavilan, Jesus; Marti, Amelia; Salas-Salvado, Jordi; Bullo, Monica, Universitat Rovira i Virgili, and Canudas, Silvia; Hernandez-Alonso, Pablo; Galie, Serena; Muralidharan, Jananee; Morell-Azanza, Lydia; Zalba, Guillermo; Garcia-Gavilan, Jesus; Marti, Amelia; Salas-Salvado, Jordi; Bullo, Monica

Published
2019

36. Higher adherence to an empirically derived Mediterranean dietary pattern is positively associated with telomere length: the Seguimiento Universidad de Navarra (SUN) project.

Author

Ojeda-Rodríguez, Ana, Zazpe, Itziar, Alonso-Pedrero, Lucia, Zalba, Guillermo, Martínez-González, Miguel A., and Marti, Amelia

Subjects
TELOMERES, WESTERN diet, MEDITERRANEAN diet, CONFIDENCE intervals, DIET, FACTOR analysis, POLYMERASE chain reaction
Abstract

Telomere integrity is influenced by oxidative stress. Also, inflammation-related factors, including nutritional factors, could modulate telomere integrity. The relationship between a posteriori-derived dietary patterns and telomere length (TL) has been scarcely investigated. Thus, our objective was to examine the association between empirically derived dietary patterns ascertained through principal component analysis (PCA) and TL in an older adult Spanish population. A total of 886 older adults (>55 years old; 645 males and 241 females) from the Seguimiento Universidad de Navarra (SUN) cohort were included in the study. TL was measured by monochrome multiplex real-time quantitative PCR. Age-adjusted TL was used for all analyses. Dietary patterns were identified by PCA based on thirty predefined candidate food groups collected from a validated 136-food items frequency questionnaire. Generalised linear models were fitted to obtain β-coefficients and their 95 % CI evaluating differences in TL between each of the four upper quintiles of adherence to dietary patterns and the lowest quintile. Sensitivity analyses by rerunning all multiple linear models under different stratifications were performed to evaluate the robustness of our results. Two major dietary patterns were empirically identified, Western dietary pattern (WDP) and Mediterranean dietary pattern (MDP). After adjustment for potential confounders, longer TL was found among subjects in the highest quintile of MDP (β = 0·064; 95 % CI 0·004, 0·123). The WDP showed no significant association with TL. In conclusion, higher adherence to a posteriori-derived MDP was independently associated with longer telomeres in an older adult Spanish population of the SUN project. [ABSTRACT FROM AUTHOR]

Published
2021
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37. Pistachio consumption modulates DNA oxidation and genes related to telomere maintenance: a crossover randomized clinical trial

Author

Canudas, Silvia, primary, Hernández-Alonso, Pablo, additional, Galié, Serena, additional, Muralidharan, Jananee, additional, Morell-Azanza, Lydia, additional, Zalba, Guillermo, additional, García-Gavilán, Jesús, additional, Martí, Amelia, additional, Salas-Salvadó, Jordi, additional, and Bulló, Mònica, additional

Published
2019
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38. Association of telomere length with IL-6 levels during an obesity treatment in adolescents: interaction with the-174G/C polymorphism in the IL-6gene

Author

García-Calzón, Sonia, Moleres, A., Gómez Martínez, Sonia, Díaz, L. E., Bueno, Gloria, Campoy, Cristina, Martínez, J. Alfredo, Marcos, Ascensión, Azcona, Cristina, Zalba, Guillermo, Martí, Amelia, Instituto de Salud Carlos III, Ministerio de Sanidad y Consumo (España), Universidad de Navarra, and Ministerio de Economía y Competitividad (España)

Subjects
Inflammation, Young population, Telomeres, Weight-loss programme
Abstract

On behalf of the EVASYON study group., [Background]: Shorter telomeres have been associated with elevated risk for age-related diseases. However, little is known about the biomarker role of telomere length (TL) for predicting inflammation and glucose alterations. [Objective]: The objective of this research is to evaluate the association between TL, inflammatory markers and glucose levels after a 2-month weight-loss programme in obese adolescents. [Methods]: Telomere length was measured using a quantitative polymerase chain reaction in 66 obese adolescents aged 12–17 years (51% men) from the EVASYON programme. The adolescents were genotyped for the polymorphism -174G/C (rs1800795) in the IL-6gene, and anthropometric and biochemical markers as well as inflammatory cytokines were analysed. [Results]: Multiple-adjusted models showed that longer telomeres at baseline were associated with a higher reduction in glucose (B = −4.08, 95% confidence interval: −6.66 to −1.50) and IL-6 (B = −1.03, 95% confidence interval: −2.01 to −0.05) serum levels after 2 months of the weight-loss treatment. The -174G/C polymorphism modulated the association between basal TL and changes in IL-6 (P interaction = 0.029). Thus, subjects with the GG + GC genotype and with longer telomeres showed a higher decrease in IL-6 levels than CC homozygotes. [Conclusion]: Longer telomeres are associated with an improvement in glucose tolerance and inflammation after a weight-loss programme in obese adolescents. Moreover, the -174G/C polymorphism may influence the relationship between TL and IL-6 changes., Research relating to this work was funded by grants from the Health Research Fund from the Carlos III Health Institute from the Ministry of Health and Consumption, Fondo de Investigacion Sanitaria (FIS; PI051579, PI051080) for the EVASYON project; Plan de Investigación Universidad de Navarra (PIUNA); Centro de Investigación Biomédica en Red (CIBER) project, CB06/03/1017, and RETICS network; and the Spanish Ministry of Economy and Competitiveness (SAF2010-20367 and SAF2013-49088-R). The FPU fellowship to García-Calzón is gratefully acknowledged.

Published
2017

39. Association of telomere length with IL-6 levels during an obesity treatment in adolescents: interaction with the-174G/C polymorphism in the IL-6gene

Author

Instituto de Salud Carlos III, Ministerio de Sanidad y Consumo (España), Universidad de Navarra, Ministerio de Economía y Competitividad (España), García-Calzón, Sonia, Moleres, A., Gómez-Martínez, Sonia, Díaz-Prieto, Ligia E., Bueno, Gloria, Campoy, Cristina, Martínez, J. Alfredo, Marcos, Ascensión, Azcona, Cristina, Zalba, Guillermo, Martí, Amelia, Instituto de Salud Carlos III, Ministerio de Sanidad y Consumo (España), Universidad de Navarra, Ministerio de Economía y Competitividad (España), García-Calzón, Sonia, Moleres, A., Gómez-Martínez, Sonia, Díaz-Prieto, Ligia E., Bueno, Gloria, Campoy, Cristina, Martínez, J. Alfredo, Marcos, Ascensión, Azcona, Cristina, Zalba, Guillermo, and Martí, Amelia

Abstract

[Background]: Shorter telomeres have been associated with elevated risk for age-related diseases. However, little is known about the biomarker role of telomere length (TL) for predicting inflammation and glucose alterations. [Objective]: The objective of this research is to evaluate the association between TL, inflammatory markers and glucose levels after a 2-month weight-loss programme in obese adolescents. [Methods]: Telomere length was measured using a quantitative polymerase chain reaction in 66 obese adolescents aged 12–17 years (51% men) from the EVASYON programme. The adolescents were genotyped for the polymorphism -174G/C (rs1800795) in the IL-6gene, and anthropometric and biochemical markers as well as inflammatory cytokines were analysed. [Results]: Multiple-adjusted models showed that longer telomeres at baseline were associated with a higher reduction in glucose (B = −4.08, 95% confidence interval: −6.66 to −1.50) and IL-6 (B = −1.03, 95% confidence interval: −2.01 to −0.05) serum levels after 2 months of the weight-loss treatment. The -174G/C polymorphism modulated the association between basal TL and changes in IL-6 (P interaction = 0.029). Thus, subjects with the GG + GC genotype and with longer telomeres showed a higher decrease in IL-6 levels than CC homozygotes. [Conclusion]: Longer telomeres are associated with an improvement in glucose tolerance and inflammation after a weight-loss programme in obese adolescents. Moreover, the -174G/C polymorphism may influence the relationship between TL and IL-6 changes.

Published
2017

41. Telomere length as a biomarker for adiposity changes after a multidisciplinary intervention in overweight/obese adolescents: the EVASYON study.

Author

García-Calzón, Sonia, Moleres, A., Marcos, Ascensión, Campoy, Cristina, Moreno, Luis A., Azcona, Cristina, Martínez-González, Miguel Ángel, Martínez, J. Alfredo, Zalba, Guillermo, Martí, Amelia, García-Calzón, Sonia, Moleres, A., Marcos, Ascensión, Campoy, Cristina, Moreno, Luis A., Azcona, Cristina, Martínez-González, Miguel Ángel, Martínez, J. Alfredo, Zalba, Guillermo, and Martí, Amelia

Abstract

CONTEXT: Telomeres are biomarkers of biological aging. Shorter telomeres have been associated with increased adiposity in adults. However, this relationship remains unclear in children and adolescents. OBJECTIVE: To evaluate the association between telomere length (TL) and adiposity markers in overweight/obese adolescents after an intensive program. We hypothesize that greater TL at baseline would predict a better response to a weight loss treatment. DESIGN SETTING PATIENTS AND INTERVENTION: The EVASYON is a multidisciplinary treatment program for adolescents with overweight and obesity that is aimed at applying the intervention to all possibly involved areas of the individual, such as dietary habits, physical activity and cognitive and psychological profiles. Seventy-four participants (36 males, 38 females, 12-16 yr) were enrolled in the intervention program: 2 months of an energy-restricted diet and a follow-up period (6 months). MAIN OUTCOME: TL was measured by quantitative real-time polymerase chain reaction at baseline and after 2 months; meanwhile, anthropometric variables were also assessed after 6 months of follow-up. RESULTS: TL lengthened in participants during the intensive period (+1.9±1.0, p<0.001) being greater in overweight/obese adolescents with the shortest telomeres at baseline (r¿=¿-0.962, p<0.001). Multivariable linear regression analysis showed that higher baseline TL significantly predicted a higher decrease in body weight (B¿=¿-1.53, p¿=¿0.005; B¿=¿-2.25, p¿=¿0.047) and in standard deviation score for body mass index (BMI-SDS) (B¿=¿-0.22, p¿=¿0.010; B¿=¿-0.47, p¿=¿0.005) after the intensive and extensive period treatment respectively, in boys. CONCLUSION: Our study shows that a weight loss intervention is accompanied by a significant increase in TL in overweight/obese adolescents. Moreover, we suggest that initial longer TL could be a potential predictor for a better weight loss response.

Published
2014

42. Galectin‐3, a Biomarker Linking Oxidative Stress and Inflammation With the Clinical Outcomes of Patients With Atherothrombosis

Author

Madrigal‐Matute, Julio, primary, Lindholt, Jes Sandal, additional, Fernandez‐Garcia, Carlos Ernesto, additional, Benito‐Martin, Alberto, additional, Burillo, Elena, additional, Zalba, Guillermo, additional, Beloqui, Oscar, additional, Llamas‐Granda, Patricia, additional, Ortiz, Alberto, additional, Egido, Jesus, additional, Blanco‐Colio, Luis Miguel, additional, and Martin‐Ventura, Jose Luis, additional

Published
2014
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45. Blockade of TGF-β1 Signalling Inhibits Cardiac NADPH Oxidase Overactivity in Hypertensive Rats

Author

Miguel-Carrasco, José Luis, primary, Baltanás, Ana, additional, Cebrián, Carolina, additional, Moreno, María U., additional, López, Begoña, additional, Hermida, Nerea, additional, González, Arantxa, additional, Dotor, Javier, additional, Borrás-Cuesta, Francisco, additional, Díez, Javier, additional, Fortuño, Ana, additional, and Zalba, Guillermo, additional

Published
2012
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50. Molecular Mechanisms of Atherosclerosis in Metabolic Syndrome

Author

González-Navarro, Herminia, primary, Vinué, Ángela, additional, Vila-Caballer, Marian, additional, Fortuño, Ana, additional, Beloqui, Oscar, additional, Zalba, Guillermo, additional, Burks, Deborah, additional, Díez, Javier, additional, and Andrés, Vicente, additional

Published
2008
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