Nuestros investigadores

Guillermo Zalba Goñi

Publicaciones científicas más recientes (desde 2010)

Autores: Canudas, S., (Autor de correspondencia); Hernandez-Alonso, P.; Galie, S.; et al.
Revista: AMERICAN JOURNAL OF CLINICAL NUTRITION
ISSN 0002-9165  Vol. 109  Nº 6  2019  págs. 1738 - 1745
Background: Telomere attrition may play an important role in the pathogenesis and severity of type 2 diabetes (T2D), increasing the probability of beta cell senescence and leading to reduced cell mass and decreased insulin secretion. Nutrition and lifestyle are known factors modulating the aging process and insulin resistance/secretion, determining the risk of T2D. Objectives: The aim of this study was to evaluate the effects of pistachio intake on telomere length and other cellular aging-related parameters of glucose and insulin metabolism. Methods: Forty-nine prediabetic subjects were included in a randomized crossover clinical trial. Subjects consumed a pistachio-supplemented diet (PD, 50 E% [energy percentage] carbohydrates and 33 E% fat, including 57 g pistachios/d) and an isocaloric control diet (CD, 55 E% carbohydrates and 30 E% fat) for 4 mo each, separated by a 2-wk washout period. DNA oxidation was evaluated by DNA damage (via 8-hydroxydeoxyguanosine). Leucocyte telomere length and gene expression related to either oxidation, telomere maintenance or glucose, and insulin metabolism were analyzed by multiplexed quantitative reverse transcriptase-polymerase chain reaction after the dietary intervention. Results: Compared with the CD, the PD reduced oxidative damage to DNA (mean: -3.5%; 95% CI: -8.07%, 1.05%; P = 0.009). Gene expression of 2 telomere-related genes (TERT and WRAP53) was significantly upregulated (164% and 53%) after the PD compared with the CD (P = 0.043 and P = 0.001, respectively). Interestingly, changes in TERT expression were negatively correlated to changes in fasting plasma glucose concentrations and in the homeostatic model assessment of insulin resistance. Conclusions: Chronic pistachio consumption reduces oxidative damage to DNA and increases the gene expression of some telomere-associated genes. Lessening oxidative damage to DNA and telomerase expression through diet may represent an intriguing way to promote healthspan in humans, reversing certain deleterious metabolic consequences of prediabetes.
Autores: Zalba, Guillermo; et al.
Revista: OBESITY FACTS
ISSN 1662-4025  Vol. 12  Nº Supl. 1  2019  págs. 56
Autores: Solas, Maite; Pejenaute, Álvaro; et al.
Revista: FREE RADICAL BIOLOGY AND MEDICINE
ISSN 0891-5849  Vol. 139  Nº S1  2019  págs. S17 - S17
Autores: Avendano, M. S.; Garcia-Redondo, A. B.; Zalba, Guillermo; et al.
Revista: HYPERTENSION
ISSN 0194-911X  Vol. 72  Nº 2  2018  págs. 492 - 502
mPGES-1 (microsomal prostaglandin E synthase-1), the downstream enzyme responsible for PGE(2) (prostaglandin E-2) synthesis in inflammatory conditions and oxidative stress are increased in vessels from hypertensive animals. We evaluated the role of mPGES-1-derived PGE(2) in the vascular dysfunction and remodeling in hypertension and the possible contribution of oxidative stress. We used human peripheral blood mononuclear cells from asymptomatic patients, arteries from untreated and Ang II (angiotensin II)-infused mPGES-1(-/-) and mPGES-1(+/+) mice, and vascular smooth muscle cells exposed to PGE(2). In human cells, we found a positive correlation between mPGES-1 mRNA and carotid intima-media thickness (r=0.637; P<0.001) and with NADPH oxidase-dependent superoxide production (r=0.417; P<0.001). In Ang II-infused mice, mPGES-1 deletion prevented all of the following: (1) the augmented wall:lumen ratio, vascular stiffness, and altered elastin structure; (2) the increased gene expression of profibrotic and proinflammatory markers; (3) the increased vasoconstrictor responses and endothelial dysfunction; (4) the increased NADPH oxidase activity and the diminished mitochondrial membrane potential; and (5) the increased reactive oxygen species generation and reduced NO bioavailability. In vascular smooth muscle cells or aortic segments, PGE(2) increased NADPH oxidase expression and activity and reduced mitochondrial membrane potential, effects that were abolished by antagonists of the PGE(2) receptors (EP), EP1 and EP3, and by JNK (c-Jun N-terminal kinase) and ERK1/2 (extracellular-signal-regulated kinases 1/2) inhibition. Deletion of mPGES-1 augmented vascular production of PGI(2) suggesting rediversion of the accumulated PGH(2) substrate. In conclusion, mPGES-1-derived PGE(2) is involved in vascular remodeling, stiffness, and endothelial dysfunction in hypertension likely through an increase of oxidative stress produced by NADPH oxidase and mitochondria.
Autores:  Garde, N.; et al.
Revista: FREE RADICAL BIOLOGY AND MEDICINE
ISSN 0891-5849  Vol. 126  2018  págs. 15 - 26
NADPH oxidase (Nox) variants Nox1, Nox2 and Nox4 are implicated in the progression of liver fibrosis. However, the role of Nox5 is not yet known, mainly due to the lack of this enzyme in rat and mouse genomes. Here we describe the expression and functional relevance of Nox5 in the human cell line of hepatic stellate cells (HSC) LX-2. Under basal conditions, three long (Nox5-L: Nox5 alpha, -beta, and -delta) and a short (Nox5-S or Nox5 epsilon) splice variants were detected, which were silenced with specific siRNAs for Nox5. The most abundant isoform was Nox5-S, accounting for more than 90% of Nox5 protein. Overexpression of Nox5 beta generated reactive oxygen species (ROS) in the presence of calcium, as judged by the production of hydrogen peroxide, L-012 luminescence and cytochrome c reduction. Nox5 epsilon did not generated ROS under these conditions, and a reduced ROS production was observed when co-expressed with Nox5 beta. In contrast, dihydroethidium oxidation was increased by Nox5 beta or Nox5 epsilon, suggesting that Nox5 epsilon induced intracellular oxidative stress by an unknown mechanism. Functional studies showed that both Nox5 beta and Nox5 epsilon stimulated the proliferation of LX-2 cells and the collagen type I levels, while Nox5 siRNAs inhibited these effects. Interestingly, TGF-beta and angiotensin II upregulated Nox5 expression, which was reduced in cells pre-incubated with catalase. Further studies silencing Nox5 in TGF-beta-treated cells resulted in a reduction of collagen levels via p38 MAPK. Collectively, these results show for the first time that Nox5 can play a relevant role in the proliferation and fibrosis on human HSC.
Autores: Roncal, Carmen; Orbe, J; et al.
Revista: ATHEROSCLEROSIS
ISSN 0021-9150  Vol. 278  2018  págs. 124 - 134
Background and aims: Matrix metalloproteinases (MMPs) have been implicated in atherosclerosis and vascular calcification. Among them, we reported that MMP10 is present in human atheroma, associated with atherosclerosis. However, it remains unclear whether MMP10 is involved in atherogenesis and vascular calcification. Methods: MMP10 was measured in serum from patients with subclinical atherosclerosis and analyzed in carotid endarterectomies by immunostaining. ApoE-deficient mice (Apoe(-/-)) were crossed to MMP10-deficient (Mmp10(-/-)) mice and followed up to 20 months. Plaque area and composition were assessed by histology and immunohistochemistry. Inflammatory markers were measured in atherosclerotic plaques by RT-qPCR, and leukocyte subpopulations were analyzed by flow cytometry. In vitro calcification assays were performed in aortic vascular smooth muscle cells (VSMC). Results: MMP10 serum levels were associated with coronary calcification in subjects with subclinical atherosclerosis. Immunostaining revealed MMP10 expression in human atheromas, spatially associated with calcification areas, and complicated plaques released higher amounts of MMP10 than non-diseased segments. Interestingly, vascular MMP10 expression was confined to the atherosclerotic lesion in Apoe(-/-) mice, and Apoe(-/-) Mmp10(-/-) showed a substantial reduction in atherosclerotic lesion size, macrophage content and plaque calcification. Reduced local and systemic inflammatory markers could be demonstrated in Apoe(-/-) Mmp10(-/-) by gene expression and flow cytometry analysis. Calcium phosphate deposition and vascular calcification markers were downregulated in VSMC from Apoe(-/-) Mmp10(-/-) mice. Conclusions: Delayed plaque progression and altered cellular composition in the absence of MMP10 suggests that MMP10 plays a role in atherosclerosis, favoring inflammation, development and complication of the plaque.
Autores: Ibarrola, J.; Arrieta, V.; Sadaba, R.; et al.
Revista: CLINICAL SCIENCE
ISSN 0143-5221  Vol. 132  Nº 13  2018  págs. 1471 - 1485
Galectin-3 (Gal-3) is increased in heart failure (HF) and promotes cardiac fibrosis and inflammation. We investigated whether Gal-3 modulates oxidative stress in human cardiac fibroblasts, in experimental animal models and in human aortic stenosis (AS). Using proteomics and immunodetection approaches, we have identified that Gal-3 down-regulated the antioxidant peroxiredoxin-4 (Prx-4) in cardiac fibroblasts. In parallel, Gal-3 increased peroxide, nitrotyrosine, malondialdehyde, and N-carboxymethyl-lysine levels and decreased total antioxidant capacity. Gal-3 decreased prohibitin-2 expression without modifying other mitochondrial proteins. Prx-4 silencing increased oxidative stress markers. In Gal-3-silenced cells and in heart fromGal-3 knockout mice, Prx-4 was increased and oxidative stress markers were decreased. Pharmacological inhibition of Gal-3 with modified citrus pectin restored cardiac Prx-4 as well as prohibitin-2 levels and improved oxidative status in spontaneously hypertensive rats. In serum from 87 patients with AS, Gal-3 negatively correlated with total antioxidant capacity and positively correlated with peroxide. In myocardial biopsies from 26 AS patients, Gal-3 up-regulation paralleled a decrease in Prx-4 and in prohibitin-2. Cardiac Gal-3 inversely correlated with Prx-4 levels in myocardial biopsies. These data suggest that Gal-3 decreased Prx-4 antioxidant system in cardiac fibroblasts, increasing oxidative stress. In pathological models presenting enhanced cardiac Gal-3, the decrease in Prx-4 expression paralleled increased oxidative stress. Gal-3 blockade restored Prx-4 expression and improved oxidative stress status. In AS, circulating levels of Gal-3 could reflect oxidative stress. The alteration of the balance between antioxidant systems and reactive oxygen species production could be a new pathogenic mechanism by which Gal-3 induces cardiac damage in HF.
Autores: Garcia-Redondo, A. B.; Avendano, M. S.; Aguado, A.; et al.
Revista: EUROPEAN JOURNAL OF CLINICAL INVESTIGATION
ISSN 0014-2972  Vol. 48  Nº Supl. 1  2018  págs. 122 - 122
Autores: Pejenaute, Álvaro; Ansorena, Eduardo; et al.
Revista: FREE RADICAL BIOLOGY AND MEDICINE
ISSN 0891-5849  Vol. 120  Nº Supl. 1  2018  págs. S101 - S101
Autores:  Garde, N. ; et al.
Revista: FREE RADICAL BIOLOGY AND MEDICINE
ISSN 0891-5849  Vol. 120  2018  págs. S86 - S86
NADPH oxidase (Nox) variants Nox1, Nox2 and Nox4 have been implicated in the progression of liver fibrosis. However, the role of Nox5 is unknown, mainly due to the lack of this enzyme in rat and mouse genomes. Here we describe the expression and functional relevance of Nox5 in the human cell line of hepatic stellate cells (HSC), LX-2. Under basal conditions, these cells expressed a long (Nox5L) and a short (Nox5S) variant which were silenced with specific siRNAs for Nox5. Overexpression of Nox5L generated ROS in the presence of calcium, as judged by the production of extracellular hydrogen peroxide, L-012 luminescence and cytochrome c reduction, while Nox5S did not generated ROS under these conditions. In contrast, dihydroethidium oxidation was increased when either Nox5L or Nox5S were overexpressed. Functional studies revealed that both Nox5L and Nox5S stimulated the proliferation of LX-2 cells and the synthesis of type I collagen, while Nox5 siRNAs inhibited these effects. Interestingly, TGF-beta and angiotensin II induced Nox5, and silencing Nox5 reduced collagen production stimulated by TGF-beta. Collectively, these results suggest for the first time that Nox5 can play a relevant role in HSC proliferation and fibrogenesis.
Autores: Beloqui, Óscar; Moreno, MU; San José, Gorka; et al.
Revista: FREE RADICAL RESEARCH
ISSN 1071-5762  Vol. 51  Nº 4  2017  págs. 389 - 396
Vascular calcification is a common feature in atherosclerosis and associates with cardiovascular events. Oxidative stress may be involved in the pathogenesis of vascular calcification. Previous studies have shown that the phagocytic NADPH oxidase is associated with atherosclerosis. The objective of the present study was to investigate the association between phagocytic NADPH oxidase-mediated superoxide production and coronary artery calcium (CAC). NADPH oxidase-mediated superoxide production was determined by chemiluminescence and CAC by computed tomography in 159 asymptomatic men free of overt clinical atherosclerosis. Multivariate linear regression analyses were used to assess the relationship between CAC and NADPH oxidase-mediated superoxide production. Compared with individuals in the lowest score of CAC (= 0 Agatston units), those in the upper score (> 400 Agatston units) showed higher superoxide production (p < 0.05). In correlation analysis, superoxide production positively (p < 0.01) correlated with CAC, which in multivariate analysis remained significant after adjusting for age, HDL-cholesterol, triglycerides, body mass index, smoking, arterial hypertension and diabetes mellitus. In conclusion, in a population of men without clinically overt atherosclerotic disease, increased NADPH oxidase-mediated superoxide production associated with enhanced CAC. Albeit descriptive, these findings suggest a potential involvement of phagocytic NADPH oxidase-mediated oxidative stress in CAC.
Autores: Beaumont Javier; San José, Gorka; Moreno, MU; et al.
Revista: SCIENTIFIC REPORTS
ISSN 2045-2322  Vol. 7  2017  págs. 41865
Excessive myocardial collagen deposition and cross-linking (CCL), a process regulated by lysyl oxidase (LOX), determines left ventricular (LV) stiffness and dysfunction. The angiotensin II antagonist losartan, metabolized to the EXP3179 and EXP3174 metabolites, reduces myocardial fibrosis and LV stiffness in hypertensive patients. Our aim was to investigate the differential influence of losartan metabolites on myocardial LOX and CCL in an experimental model of hypertension with myocardial fibrosis, and whether EXP3179 and EXP3174 modify LOX expression and activity in fibroblasts. In rats treated with NG-nitro-L-arginine methyl ester (L-NAME), administration of EXP3179 fully prevented LOX, CCL and connective tissue growth factor (CTGF) increase, as well as fibrosis, without normalization of blood pressure (BP). In contrast, administration of EXP3174 normalized BP and attenuated fibrosis but did not modify LOX, CCL and CTGF. In TGF-beta(1)-stimulated fibroblasts, EXP3179 inhibited CTGF and LOX expression and activity with lower IC50 values than EXP3174. Our results indicate that, despite a lower antihypertensive effect, EXP3179 shows higher anti-fibrotic efficacy than EXP3174, likely through its ability to prevent the excess of LOX and CCL. It is suggested that the anti-fibrotic effect of EXP3179 may be partially mediated by the blockade of CTGF-induced LOX in fibroblasts.
Autores: Moleres, A.; Gómez-Martinez, S.; et al.
Revista: PEDIATRIC OBESITY
ISSN 2047-6310  Vol. 12  Nº 3  2017  págs. 257 - 263
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.
Autores: Martínez, Miguel Ángel; Razquin, Cristina; et al.
Revista: CLINICAL NUTRITION
ISSN 0261-5614  Vol. 35  Nº 6  2016  págs. 1399 - 1405
Background & aims A healthy lifestyle has been associated with longer telomeres, but whether Mediterranean Diet (MeDiet) affect telomere length (TL) has not been fully elucidated yet. Our aim was to assess the relationship between MeDiet and TL in high cardiovascular risk subjects in the context of a randomized nutritional intervention trial. Methods We assessed 520 participants (55¿80 years, 55% women) from the PREDIMED-NAVARRA trial. Leukocyte TL was measured by qPCR at baseline and after 5 years of a dietary intervention program where subjects were randomly assigned to a low-fat control diet or to two MeDiets, one supplemented with extra virgin olive oil (MeDiet-EVOO) and the other with mixed nuts (MeDiet-nuts). A validated 14-item questionnaire was used to appraise baseline adherence of participants to the MeDiet. Results Better adherence to MeDiet (as appraised by the 14-item score) was associated with longer basal telomeres in women in the baseline cross-sectional analysis, whereas the opposite was observed in men (P interaction = 0.036). Female subjects who scored 10 points had longer basal telomeres (0.27, 95% CI: 0.03¿0.52) than women scoring ¿6 points at the beginning of the study (¿0.46, 95% CI: ¿0.85 to ¿0.7) (P = 0.003). However, allocation to the MeDiet-nuts group (¿0.24, 95% CI: ¿0.38 to ¿0.01) was associated with a higher risk of telomere shortening after 5 years of intervention, whereas no differences were found for the MeDiet-EVOO group (0.14, 95% CI: 0.02¿0.27), in comparison with the Control group (0.07, 95% CI: ¿0.08 to 0.23) (P = 0.003 and P = 0.537, respectively). Conclusion A greater baseline adherence to a Mediterranean dietary pattern was associated with longer telomeres only in women. No beneficial effect of the intervention with the MeDiet for the prevention of telomere shortening in comparison with a low-fat diet was observed.
Autores: Gómez, Sara; et al.
Revista: OBESITY FACTS
ISSN 1662-4025  Vol. 9  Nº Supl. 1  2016  págs. 103
Autores: Madrigal-Matute, J.; Fernandez-Garcia, C. E.; Blanco-Colio, L. M.; et al.
Revista: FREE RADICAL BIOLOGY AND MEDICINE
ISSN 0891-5849  Vol. 86  2015  págs. 352 - 361
To assess the potential association between TRX-1/PRX-1 and NADPH oxidase (Nox) activity in vivo and in vitro, TRX-1/PRX-1 levels were assessed by ELISA in 84 asymptomatic subjects with known phagocytic NADPH oxidase activity and carotid intima-media thickness (IMT). We found a positive correlation between TRX-1/PRX-1 and NADPH oxidase-dependent superoxide production (r=0.48 and 0.47; p<0.001 for both) and IMT (r=0.31 and 0.36; p<0.01 for both) adjusted by age and sex. Moreover, asymptomatic subjects with plaques have higher PRX-1 and TRX plasma levels (p<0.01 for both). These data were confirmed in a second study in which patients with carotid atherosclerosis showed higher PRX-1 and TRX plasma levels than healthy subjects (p<0.001 for both). In human atherosclerotic plaques, the NADPH oxidase subunit p22phox colocalized with TRX-1/PRX-1 in macrophages (immunohistochemistry). In monocytes and macrophages, phorbol 12-myristate 13-acetate (PMA) induced NADPH activation and TRX-1/PRX-1 release to the extracellular medium, with a concomitant decrease in their intracellular levels, which was reversed by the NADPH inhibitor apocynin (Western blot). In loss-of-function experiments, genetic silencing of the NADPH oxidase subunit Nox2 blocked PMA-induced intracellular TRX-1/PRX-1 downregulation in macrophages. Furthermore, the PMA-induced release of TRX-1/PRX-1 involves the modulation of their redox status and exosome-like vesicles. TRX-1/PRX-1 levels are associated with NADPH oxidase-activity in vivo and in vitro. These data could suggest a coordinated antioxidant response to oxidative stress in atherothrombosis.
Autores: Madrigal-Matute, J.; Fernandez-Laso, V.; Sastre, C.; et al.
Revista: CARDIOVASCULAR RESEARCH
ISSN 1755-3245  Vol. 108  Nº 1  2015  págs. 139 - 147
AIM: The interaction between TNF-like weak inducer of apoptosis (TWEAK, Tnfsf12) and the receptor, fibroblast growth factor-inducible 14 (Fn14), regulates vascular damage through different mechanisms, including inflammation. Oxidative stress plays a major role in inflammation and the development of atherosclerosis, but the relationship between TWEAK and oxidative stress is, however, poorly understood. METHODS AND RESULTS: In this study, we found that TWEAK and Fn14 are co-localized with the NADPH subunits, p22phox and Nox2, in human advanced atherosclerotic plaques. Using primary human macrophages and a murine macrophage cell line, we demonstrate that TWEAK promotes ROS production and enhances NADPH oxidase activity. Hence, we show a direct involvement of the TWEAK-Fn14 axis in oxidative stress, as genetic silencing of Fn14 or Nox2 abrogates the TWEAK-induced ROS production. Furthermore, our results point at Rac1 as an upstream mediator of TWEAK during oxidative stress. Finally, using an in vivo murine model we confirmed the major role of TWEAK in oxidative stress, as genetic silencing of Tnfsf12 in an ApoE(-/-) background reduces the number of DHE and 8-hydroxydeoxyguanosine-positive macrophages by 50%. CONCLUSIONS: Our results suggest that TWEAK regulates vascular damage by stimulating ROS production in an Nox2-dependent manner. These new insights into the TWEAK/Fn14 axis underline their potential use as therapeutic targets in atherosclerosis.
Autores: Martínez, Miguel Ángel; et al.
Revista: CLINICAL NUTRITION
ISSN 0261-5614  Vol. 34  Nº 4  2015  págs. 694 - 699
Background & Aims: Oxidative stress and inflammation seem to be potential underlying mechanisms for telomere attrition. A lack of specific antioxidants is believed to increase free radical damage and a greater risk for telomere shortening. Our aim was to evaluate the relationship between diet and leukocyte telomere length in a cross-sectional study of children and adolescents. We hypothesized that dietary total antioxidant capacity would be positively associated with telomere length. Methods: Telomere length was measured by quantitative real-time polymerase chain reaction in 287 participants (55% males, 6¿18 years), who were randomly selected from the GENOI study. Results: A positive correlation between dietary total antioxidant capacity and telomere length (r=0.157, p=0.007) was found after adjustment for age and energy intake. However, higher white bread consumption was associated with shorter telomeres (ß=-0.204, p=0.002) in fully-adjusted models. Interestingly, those individuals who had simultaneously higher dietary total antioxidant capacity and lower white bread consumption significantly presented the longest telomeres. Moreover, the multivariable-adjusted odds ratio for very short telomeres was 0.30 for dietary total antioxidant capacity (p=0.023) and 1.37 for white bread (p=0.025). Conclusion: It was concluded that longer telomeres were associated with higher dietary total antioxidant capacity and lower white bread consumption in S2panish children and adolescents. These findings might open a new line of investigation about the potential role of an antioxidant diet in maintaining telomere length.
Autores: Zalba, Guillermo; Ruiz-Canela, M.; et al.
Revista: AMERICAN JOURNAL OF CLINICAL NUTRITION
ISSN 0002-9165  Vol. 102  Nº 4  2015  págs. 897 - 904
BACKGROUND: Dietary factors can affect telomere length (TL), a biomarker of aging, through oxidation and inflammation-related mechanisms. A Dietary Inflammatory Index (DII) could help to understand the effect of the inflammatory potential of the diet on telomere shortening. OBJECTIVE: This study aimed to determine the association of the DII with TL and to examine whether diet-associated inflammation could modify the telomere attrition rate after a 5-y follow-up of a Mediterranean dietary intervention. DESIGN: This was a prospective study of 520 participants at high cardiovascular disease risk (mean ± SD age: 67.0 ± 6.0 y, 45% males) from the PREDIMED-NAVARRA (PREvencion con DIeta MEDiterranea-NAVARRA) trial. Leukocyte TL was measured by quantitative real-time polymerase chain reaction at baseline and after 5 y of follow-up. The DII was calculated from self-reported data by using a validated 137-item food-frequency questionnaire. RESULTS: Longer telomeres at baseline were found in participants who had a more anti-inflammatory diet (lowest DII score) (P-trend = 0.012). Longitudinal analyses further showed that a greater anti-inflammatory potential of the diet (i.e., a decrease in the DII) could significantly slow down the rate of telomere shortening. Moreover, the multivariable-adjusted OR for short telomeres (z score ¿20th percentile) was 1.80 (95% CI: 1.03, 3.17) in a comparison between the highest (proinflammatory) and the lowest (anti-inflammatory) DII tertiles. Similarly, a greater DII (greatest proinflammatory values) after a 5-y follow-up was associated with almost a 2-fold higher risk of accelerated telomere attrition compared with the highest decrease in DII (greatest anti-inflammatory values) during this period (P-trend = 0.025). CONCLUSIONS: This study showed both cross-sectional and longitudinal associations between the inflammatory potential of the diet and telomere shortening in subjects with a high cardiovascular disease risk. Our findings are consistent with, but do not show, a beneficial effect of adherence to an anti-inflammatory diet on aging and health by slowing down telomere shortening. These results suggest that diet might play a key role as a determinant of TL through proinflammatory or anti-inflammatory mechanisms. This trial was registered at controlled-trials.com as ISRCTN35739639. 2015 American Society for Nutrition.
Autores: Martínez, Miguel Ángel; Razquin, Cristina; et al.
Revista: CIRCULATION-CARDIOVASCULAR GENETICS
ISSN 1942-325X  Vol. 8  Nº 1  2015  págs. 91 - 99
García-Calzón S, Martinez-González MA, Razquin C, Corella D, Salas-Salvadó J, Martinez JA, Zalba G, Marti A. Background: The gene variant Pro/Ala (rs1801282) in the PPAR¿2 has been associated with lower cardiovascular risk and greater benefit from lifestyle interventions. This polymorphism also seems to be associated with longer lifespan, but no information on telomere length (TL) is available. Our aim was to study the association between the Ala allele and changes in TL in high cardiovascular risk subjects, and the potential interaction with a Mediterranean Diet (MeDiet) pattern. Methods and Results: A total of 521 subjects (55-80 years) participating in the Prevención con Dieta Mediterránea (PREDIMED) randomized trial were genotyped. Changes in TL, measured by quantitative real-time PCR, were assessed over 5 years of a nutritional intervention which promoted adherence to the MeDiet. Interestingly, Ala carriers showed lower telomere shortening after 5 years, compared with the Pro/Pro genotype (P=0.031). This association was modulated by MeDiet since those Ala carriers who reported better conformity to the MeDiet exhibited increased TL (P<0.001). Moreover, a reduction in carbohydrate intake (¿9.5 g/d) resulted in increased TL among Ala carriers. Notably, an apparent gene-diet interaction was found through the observed changes in the MUFA+PUFA/Carbohydrates ratio: as this ratio increased, TL lengthening was detected to a greater extent in the Ala carriers compared with the Pro/Pro subjects (P for interaction <0.001). Conclusions: The Pro12Ala polymorphism is associated with TL homeostasis after 5 years follow-up in subjects at high cardiovascular risk. In addition, a higher adherence to the MeDiet
Autores: A. Marcos; et al.
Revista: PLOS ONE
ISSN 1932-6203  Vol. 9  Nº 2  2014  págs. e89828
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.
Autores: Moreno, MU; San José, Gorka; Pejenaute, Á.; et al.
Revista: HYPERTENSION
ISSN 0194-911X  Vol. 63  Nº 3  2014  págs. 468 - 474
Left ventricular hypertrophy (LVH) is an independent marker of mortality in hypertension. Although the mechanisms contributing to LVH are complex, inflammation and oxidative stress may favor its development. We analyzed the association of the phagocytic NADPH oxidase-mediated superoxide anion release and LVH in patients with essential hypertension and the role of cardiotrophin-1 (CT-1) and interleukin-6 (IL-6), cytokines implicated in cardiac growth. Blood pressure, echocardiography data, and serum CT-1 and IL-6 levels were obtained in 140 subjects: 18 normotensives without LVH, 42 hypertensives without LVH, and 80 hypertensives with LVH. The NADPH oxidase-dependent superoxide production was assessed by chemiluminescence in peripheral blood mononuclear cells. Peripheral blood mononuclear cells were stimulated with CT-1 in vitro. Superoxide anion production by peripheral blood mononuclear cells associated with LVH and correlated with the left ventricular mass index. Serum CT-1 and IL-6 levels, which associated with the left ventricular mass index, correlated with superoxide production. Serum CT-1 and IL-6 levels were correlated. CT-1 stimulated NADPH oxidase superoxide production in peripheral blood mononuclear cells, which resulted in an increased release of IL-6. Our results show that superoxide anion production by the phagocytic NADPH oxidase associates with hypertensive heart disease, being significantly enhanced in hypertensive patients with LVH. This may be attributable to the activation of the NADPH oxidase by CT-1 and the subsequent release of IL-6. The phagocytic NADPH oxidase may be a therapeutic target in hypertensive heart disease.
Autores: A. Gea; Razquin, Cristina; et al.
Revista: INTERNATIONAL JOURNAL OF OBESITY
ISSN 0307-0565  Vol. 38  2014  págs. 177 - 182
Background:Telomeres are nucleoprotein structures that protect the ends of eukaryote chromosomes. Shorter telomere length (TL) is associated with some age-related human disorders, but its relationship with obesity or adiposity parameters remains unclear.Objective:The aim of this study was to assess the relationship between TL and changes in adiposity indices after a 5-year nutritional intervention.Design and subjects:TL was measured by quantitative real-time PCR in 521 subjects (55-80 years, 55% women). Participants were randomly selected from the PREDIMED-NAVARRA centre after they completed a 5-year intervention programme. Anthropometric parameters were directly measured by trained personnel at baseline and on a yearly basis thereafter. TL at baseline and changes in TL after a 5-year intervention were assessed.Results:Higher baseline TL significantly predicted a greater decrease in body weight (B=-1.09¿kg, 95% confidence interval (CI): -2.01 to -0.16), body mass index (BMI) (B=-0.47¿kg¿m(-2), 95% CI: -0.83 to -0.11), waist circumference (B=-1.15¿cm, 95% CI: -2.28 to -0.01) and waist to height ratio (B=-0.008, 95% CI: -0.010 to -0.001) in multiple-adjusted models. In addition, changes in TL during the 5-year intervention were inversely associated with changes in the four anthropometric variables. The reduction in adiposity indices during the intervention, associated with increasing TL, was even higher among subjects with the longest telomeres at baseline. Logistic regression analysis showed that the risk of remaining obese after 5 years was lower in those participants who initially had the longest telomeres and increased their TL after intervention (odds ratio=0.27, 95% CI: 0.03-2.03).Conclusions:Our research suggests that TL is inversely associated with changes in obesity parameters. The assessment of TL can provide further insights for biological pathways leading to adiposity. We show for the first time an improvement of obesity indices when an increase in TL is observed after a 5-year Mediterranean diet intervention.
Autores: Madrigal-Matute, J.; Lindholt, J. S.; Fernandez-Garcia, C. E.; et al.
Revista: AMERICAN HEART ASSOCIATION. JOURNAL. CARDIOVASCULAR AND CEREBROVASCULAR DISEASE
ISSN 2047-9980  Vol. 3  Nº 4  2014  págs. e000785
BACKGROUND: Galectin-3 (Gal-3) participates in different mechanisms involved in atherothrombosis, such as inflammation, proliferation, or macrophage chemotaxis. Thus, there have been committed intensive efforts to elucidate the function of Gal-3 in cardiovascular (CV) diseases. The role of Gal-3 as a circulating biomarker has been demonstrated in patients with heart failure, but its importance as a biomarker in atherothrombosis is still unknown. METHODS AND RESULTS: Because Gal-3 is involved in monocyte-to-macrophage transition, we used fresh isolated monocytes and the in vitro model of macrophage differentiation of THP-1 cells stimulated with phorbol myristate acetate (PMA). Gal-3 release is increased by PMA in human monocytes and macrophages, a process involving exosomes and regulated by reactive oxygen species/NADPH oxidase activity. In asymptomatic subjects (n=199), Gal-3 plasma levels are correlated with NADPH oxidase activity in peripheral blood mononuclear cells (r=0.476; P<0.001) and carotid intima-media thickness (r=0.438; P<0.001), a surrogate marker of atherosclerosis. Accordingly, Gal-3 plasma concentrations are increased in patients with carotid atherosclerosis (n=158), compared to control subjects (n=115; 14.3 [10.7 to 16.9] vs. 10.4 [8.6 to 12.5] ng/mL; P<0.001). Finally, on a 5-year follow-up study in patients with peripheral artery disease, Gal-3 concentrations are significantly and independently associated with an increased risk for CV mortality (hazard ratio=2.24, 95% confidence interval: 1.06 to 4.73, P<0.05). CONCLUSIONS: Gal-3 extracellular levels could reflect key underlying mechanisms involved in atherosclerosis etiology, development, and plaque rupture, such as inflammation, infiltration of circulating cells and oxidative stress. Moreover, circulating Gal-3 concentrations are associated with clinical outcomes in patients with atherothrombosis.
Autores: San José, Gorka; Moreno, MU; et al.
Revista: ANTIOXIDANTS AND REDOX SIGNALING
ISSN 1523-0864  Vol. 19  Nº 14  2013  págs. 1607 - 1618
Aims: The NADPH oxidases constitute a major source of superoxide anion (·O2¿) in hypertension. Several studies suggest an important role of NADPH oxidases in different effects mediated by transforming growth factor-ß1 (TGF-ß1). We investigated whether a chronic treatment with P144, a peptide synthesized from type III TGF-ß1 receptor, inhibited NADPH oxidases in the renal cortex of spontaneously hypertensive rats (SHR). Results: Here, we show that chronic administration of P144 significantly reduced the NADPH oxidase expression and activity as well as the oxidative stress observed in control vehicle-treated SHR (V-SHR). In addition, P144 was also able to reduce the significant increase in the renal fibrosis and in mRNA expression of different components of collagen metabolism, as well as in the levels of connective tissue growth factor observed in V-SHR. Finally, TGF-ß1-stimulated NRK52E exhibited a significant increase in NADPH oxidase expression and activity as well as a TGF-ß1-dependent intracellular pathway that were inhibited in the presence of P144. Innovation: Our experimental evidence suggests that reversing oxidative stress may be therapeutically useful in preventing fibrosis-associated renal damage. We show here that (i) the TGF-ß1-NADPH oxidases axis is crucial in the development of fibrosis in an experimental hypertensive renal disease animal model, and (ii) the use of P144 reverses TGF-ß1-dependent NADPH oxidase activity; thus, P144 may be considered a novel therapeutic tool in kidney disease associated with hypertension. Conclusion: We demonstrate that P144 inhibits NADPH oxidases and prevents oxidative stress in kidneys from hypertensive rats. Our data also suggest that these effects are associated with the renal antifibrotic effect of P144.
Autores: Moreno, MU; López, B; González, A; et al.
Revista: CLINICAL SCIENCE
ISSN 0143-5221  Vol. 125  Nº 6  2013  págs. 291 - 300
The NADPH oxidases are a key family of ROS (reactive oxygen species)-producing enzymes which may differentially contribute to cardiac pathophysiology. Animal studies show uncertain results regarding the regulation of cardiac Nox4 by pressure overload and no data are available on human myocardial Nox4. In the present study, we evaluated Nox4 expression and its relationship with myocardial remodelling and LV (left ventricular) function in patients with severe AS (aortic valve stenosis). Endomyocardial biopsies from 34 patients with AS were obtained during aortic valve replacement surgery. LV morphology and function were assessed by echocardiography. Myocardial samples from subjects deceased of non-CVDs (cardiovascular diseases) were analysed as controls. Nox4 localization was evaluated by immunohistochemistry and quantified by Western blot. Myocardial capillary density, fibrosis and cardiomyocyte dimensions and apoptosis were assessed histologically to evaluate myocardial remodelling. Nox4 was present in samples from all subjects and expressed in cardiomyocytes, VSMCs (vascular smooth muscle cells), endothelium and fibroblasts. Nox4 levels were reduced 5-fold in AS patients compared with controls (P<0.01). Nox4 levels directly correlated with cardiomyocyte cross-sectional area (r=0.299, P<0.05) and diameter (r=0.406, P<0.05) and capillary density (r=0.389, P<0.05), and inversely with cardiomyocyte apoptosis (r=-0.316, P<0.05) in AS patients. In addition, Nox4 levels correlated with echocardiographic parameters (LV ejection fraction: r=0.353, P<0.05; midwall fractional shortening: r=0.355, P<0.05; deceleration time: r=-0.345, P<0.05) in AS patients. Nox4 is expressed in human myocardium and reduced in AS patients. The observed associations of Nox4 with cardiomyocyte parameters and capillary density in AS patients suggest a potential role of Nox4 deficiency in the myocardial remodelling present in the human pressure-overloaded heart.
Autores: Solesio, M. E.; Zalba, Guillermo; et al.
Revista: JOURNAL OF PHYSIOLOGY AND BIOCHEMISTRY
ISSN 1138-7548  Vol. 69  Nº 4  2013  págs. 927 - 935
Herein, we investigate whether the NADPH oxidase might be playing a key role in the degree of oxidative stress in the senescence-accelerated mouse prone-8 (SAM-P8). To this end, the activity and expression of the NADPH oxidase, the ratio of glutathione and glutathione disulfides (GSH/GSSG), and the levels of malonyl dialdehyde (MDA) and nitrotyrosine (NT) were determined in renal tissue from SAM-P8 mice at the age of 1 and 6 months. The senescence-accelerated-resistant mouse (SAM-R1) was used as control. At the age of 1 month, NADPH oxidase activity and Nox2 protein expression were higher in SAM-P8 than in SAM-R1 mice. However, we found no differences in the GSH/GSSG ratio, MDA, NT, and Nox4 levels between both groups of animals. At the age of 6 months, SAM-R1 mice in comparison to SAM-P8 mice showed an increase in NADPH oxidase activity, which is associated with higher levels of NT and increased Nox4 and Nox2 expression levels. Furthermore, we found oxidative stress hallmarks including depletion in GSH/GSSG ratio and increase in MDA levels in the kidney of SAM-P8 mice. Finally, NADPH oxidase activity positively correlated with Nox2 expression in all the animals (r¿=¿0.382, P¿<¿0.05). Taken together, our data allow us to suggest that an increase in NADPH oxidase activity might be an early hallmark to predict future oxidative stress in renal tissue during the aging process that takes place in SAM-P8 mice.
Autores: Ravassa, S; Beloqui, Óscar; Varo, N; et al.
Revista: JOURNAL OF HYPERTENSION
ISSN 0263-6352  Vol. 31  Nº 3  2013  págs. 587 - 594
Objectives: Cardiotrophin-1 (CT-1) induces hypertrophic growth and contractile dysfunction in cardiomyocytes. This cross-sectional study was aimed to analyze CT-1 associations with echocardiographically assessed left ventricular systolic properties taking into account the influence of left ventricular growth [i.e. left ventricular hypertrophy (LVH) and inappropriate left ventricular mass (iLVM)] in asymptomatic hypertensive patients. Methods: Serum CT-1 was measured by ELISA in 278 asymptomatic hypertensive patients with a left ventricular ejection fraction more than 50% and in 25 age and sex-matched normotensive patients. Results: Serum CT-1 was increased in hypertensive patients as compared to normotensive patients. CT-1 was directly correlated with parameters of left ventricular mass (LVM) and inversely correlated with parameters assessing myocardial systolic function and left ventricular chamber contractility in hypertensive patients, these associations being independent of a number of potential confounding factors. Interestingly, the associations of CT-1 with myocardial systolic function were independent of LVM even in patients with LVH or iLVM. In addition, there was a significant increment of serum CT-1 in hypertensive patients with LVH or iLVM, especially in those in whom LVH or iLVM were accompanied by impaired myocardial systolic function, as compared to the remaining hypertensive patients and normotensive patients. Plasma amino-terminal pro-brain natriuretic peptide was not correlated with any of the assessed left ventricular systolic parameters in either group of patients. Conclusion: These findings suggest that serum CT-1 is associated with myocardial systolic dysfunction in asymptomatic hypertensive patients, independently of LVM, even in those patients with pathologic left ventricular growth.
Autores: Vallvé, J. C.; Serra, N.; Zalba, Guillermo; et al.
Revista: PLOS ONE
ISSN 1932-6203  Vol. 7  Nº 8  2012  págs. e43051
Arterial stiffness is an important factor in hypertension. Fibulin 2 is an extracellular matrix scaffold protein involved in arterial stiffness and, hence, the fibulin 2 (FBLN2) gene may be a candidate for hypertension susceptibility. 4 single nucleotide polymorphisms (SNPs) of FBLN2 were evaluated in an association case-control study containing 447 hypertensive patients and 344 normotensive control subjects. The minor allele frequencies of rs3732666 and rs1061376 were significantly lower in hypertensives. The odds ratios (OR) for having the protective G (rs3732666) and T (rs1061376) alleles were 0.75 (95%CI: 0.58 to 0.96) and 0.83 (95%CI: 0.66 to 1.02), respectively. For rs3732666, the OR for hypertension in AG+GG subjects, compared with AA, was 0.71 (95%CI: 0.52 to 0.95). The protective genotype AG+GG was associated with significantly lower systolic blood pressure (SBP) [-3.6 mmHg (P = 0.048)]. There was a significant age interaction with rs3732666; the effect decreasing with increasing age. For rs1061376, TT subjects had an OR for hypertension of 0.53 (95%CI: 0.32 to 0.87) compared with CC subjects, with reduced SBP (-7.91 mmHg; P = 0.008) and diastolic BP (DBP) (-3.69 mmHg; P = 0.015). The presence of a G allele was an independent predictor of intima-media thickness (IMT); G carrier's having lower mean IMT (-0.037 mm, P = 0.027) compared with AA. Our results provide the first evidence for FBLN2 as a new gene associated with hypertension
Autores: Martín, A.; Pérez-Girón, J.V.; Hernanz, R.; et al.
Revista: JOURNAL OF HYPERTENSION
ISSN 1473-5598  Vol. 30  Nº 2  2012  págs. 315 - 326
Aims: Hypertension is associated with increased plasma inflammatory markers such as cytokines and increased vascular cyclooxygenase-2 (COX-2) expression. The ability of peroxisome proliferator-activated receptor-gamma (PPAR gamma) agonists to reduce oxidative stress seems to contribute to their anti-inflammatory properties. This study analyzes the effect of pioglitazone, a PPAR gamma agonist, on interleukin-1 beta-induced COX-2 expression and the role of reactive oxygen species (ROS) on this effect. Methods and results: Vascular smooth muscle cells from hypertensive rats stimulated with interleukin-1 beta (10 ng/ml, 24 h) were used. Interleukin-1 beta increased: 1) COX-2 protein and mRNA levels; 2) protein and mRNA levels of the NADPH oxidase subunit NOX-1, NADPH oxidase activity and ROS production; and 3) phosphorylation of inhibitor of nuclear factor kappa B (I kappa B) kinase (IKK) nuclear expression of the p65 nuclear factor kappa B (NF-kappa B) subunit and cell proliferation, all of which were reduced by apocynin (30 mu mol/l). Interleukin-1 beta-induced COX-2 expression was reduced by apocynin, tempol (10 mu mol/l), catalase (1000 U/ml) and lactacystin (5 mu mol/l). Moreover, H(2)O(2) (50 mu mol/l, 90 min) induced COX-2 expression, which was reduced by lactacystin. Pioglitazone (10 mu mol/l) reduced the effects of interleukin-1 beta on: 1) COX-2 protein and mRNA levels; 2) NOX-1 protein and mRNA levels, NADPH oxidase activity and ROS production; and 3) p-IKK, p65 expressions and cell proliferation. Pioglitazone also reduced the H(2)O(2)-induced COX-2 expression and increased Cu/Zn and Mn-superoxide dismutase protein expression. PPAR gamma small interfering RNA (5 nmol/l) further increased interleukin-1 beta-induced COX-2 and NOX-1 mRNA levels. In addition, pioglitazone increased the interleukin-1 beta-induced PPAR gamma mRNA levels. Conclusion: PPAR gamma activation with pioglitazone reduces interleukin-1 beta-induced COX-2 expression by interference with the redox-sensitive transcription factor NF-kappa B.
Autores: Moreno, MU; López, B; et al.
Revista: OXIDATIVE MEDICINE AND CELLULAR LONGEVITY
ISSN 1942-0900  Vol. 2012  Nº 2012  2012  págs. 8 p.
NADPH oxidases constitute a major source of superoxide anion (center dot O-2(-)) in hypertension. Several studies suggest an important role of NADPH oxidases in different effects mediated by TGF-beta 1. In this study we show that chronic administration of P144, a peptide synthesized from type III TGF-beta(1) receptor, significantly reduced the cardiac NADPH oxidase expression and activity as well as in the nitrotyrosine levels observed in control spontaneously hypertensive rats (V-SHR) to levels similar to control normotensive Wistar Kyoto rats. In addition, P144 was also able to reduce the significant increases in the expression of collagen type I protein and mRNA observed in hearts from V-SHR. In addition, positive correlations between collagen expression, NADPH oxidase activity, and nitrotyrosine levels were found in all animals. Finally, TGF-beta 1-stimulated Rat-2 exhibited significant increases in NADPH oxidase activity that was inhibited in the presence of P144. It could be concluded that the blockade of TGF-beta 1 with P144 inhibited cardiac NADPH oxidase in SHR, thus adding new data to elucidate the involvement of this enzyme in the profibrotic actions of TGF-beta 1.
Autores: Moreno, MU; San José, Gorka; Fortuño, Ana; et al.
Revista: FRONTIERS IN BIOSCIENCE (ELITE EDITION)
ISSN 1945-0494  Vol. 3  2011  págs. 1467 - 1474
Oxidative stress is implicated in diabetes. The NADPH oxidases are the main source of superoxide in phagocytic and vascular cells, and p22phox is a key subunit. Genetic variants of CYBA, the human p22phox gene, associate with cardiovascular disease. We investigated the association of the A640G polymorphism with diabetes and its impact on phagocytic NADPH oxidase-dependent superoxide production and subclinical atherosclerosis. We studied 1212 subjects in which clinical parameters including carotid intima-media thickness (cIMT) were assessed. The A640G polymorphism was genotyped by TaqMan probes. In 496 subjects, the NADPH oxidase-dependent superoxide production in peripheral blood mononuclear cells was assessed by chemiluminescence. The GG genotype prevalence was significantly higher in type 2 diabetic patients than in non-diabetic subjects. Peripheral blood mononuclear cells from diabetic GG patients presented higher NADPH oxidase-dependent superoxide production than those of diabetic AA/AG patients. Within the diabetic group, GG patients presented higher cIMT levels than AA/AG patients. The A640G CYBA polymorphism may be a marker of oxidative stress risk and may be indicative of subclinical atherosclerosis in type 2 diabetes.
Autores: Landecho, Manuel Fortún; Colina, María Inmaculada; Huerta, Ana; et al.
Revista: REVISTA ESPAÑOLA DE CARDIOLOGIA
ISSN 0300-8932  Vol. 64  Nº 5  2011  págs. 373-378
Insulin resistance and all metabolic syndrome traits except low level of high-density lipoproteins were significantly associated with an increased OR for EKD. Both metabolic syndrome and EKD were independently and additively related to the presence of surrogate markers of arteriosclerosis
Autores: Beaumont Javier; López, B; et al.
Revista: JOURNAL OF HYPERTENSION
ISSN 0263-6352  Vol. 29  Nº 5  2011  págs. 876 - 883
Objective: To analyze whether genetic variants of PPARA are associated with the development of stage C heart failure. Methods: We analyzed the distribution of the rs1800206, rs4253778 and rs135551 polymorphisms in genomic DNA extracted from peripheral blood cells of 534 patients in different heart failure stages and 63 healthy individuals. The mRNA expression of the peroxisome proliferator-activated receptor (PPAR)¿ target genes long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) and medium-chain acyl-CoA dehydrogenase (MCAD) was measured in myocardial biopsies of a subgroup of stage B and C patients. Functional studies were performed in HL-1 cardiomyocytes. Results: The V162 allele of the rs1800206 polymorphism was more frequent in stage C patients than in stage A and B patients and healthy individuals. Patients with the V162 allele exhibited decreased myocardial LCHAD and MCAD mRNA expression as compared to L162 homozygote patients. In addition, stage C patients exhibited lower myocardial LCHAD and MCAD mRNA expression than stage B patients. Cardiomyocytes transfected with the V162 allele presented decreased PPAR¿ transcriptional activity, LCHAD mRNA expression and ATP production compared to cardiomyocytes transfected with the L162 variant. Conclusions: These findings suggest that the V162 allele of the human PPARA gene can be a new risk factor in the development of stage C heart failure, likely via depressed cardiac PPARalfa activity.
Autores: San José, Gorka; Rodríguez, C.; et al.
Revista: CARDIOVASCULAR RESEARCH
ISSN 0008-6363  Vol. 92  Nº 2  2011  págs. 247 - 255
Aims Cardiotrophin-1 (CT-1) is a cytokine of the interleukin-6 superfamily which is up-regulated in cardiac diseases, in part via hypoxia-dependent mechanisms. However, no evidence for a direct regulation of CT-1 gene (CTF1) promoter by hypoxia inducible factor-1 (HIF-1) has been provided. Methods and results Hypoxia increased CT-1 mRNA levels in the murine adult cardiomyocyte cell line HL-1 in a time-dependent manner. Interestingly, in a murine model (C57BL/6), we show that systemic hypoxia also significantly up-regulated CT-1 in myocardial tissue. The effect of hypoxia on CT-1 expression was mediated through a transcriptional mechanism, since hypoxia increased luciferase activity of constructs containing CTF1 promoter sequences. The increase in CT-1 levels was significantly reduced by drugs that prevent calcium mobilization, such as lercanidipine, or that inhibit the activation of the PI3K/Akt pathway (wortmannin) or mammalian target of rapamycin (rapamycin). The CT-1 elevation was similarly induced by HIF-1 alpha over-expression in co-transfection experiments and prevented by HIF-1 alpha silencing. The direct interaction of HIF-1 alpha with the CTF1 promoter was confirmed through site-directed mutagenesis of hypoxia response elements, electrophoreric mobility shift, and ChIP assays. Hypoxia induced HL-1 apoptosis (measured as annexin-V binding or caspase 3/7 activity) which was increased when CT-1 was silenced in knocked-down cells by lentiviral vectors. Conclusion Hypoxia increased CT-1 levels in cardiac cells (in vitro and in vivo) through a direct regulation of CTF1 promoter by HIF-1 alpha. This CT-1 activation by hypoxia may protect cells from apoptosis, thus supporting a protective role for CT-1 as a survival factor for cardiomyocytes.
Autores: Landecho, Manuel Fortún; Fortuño, Ana; Zalba, Guillermo; et al.
Revista: REVISTA ESPAÑOLA DE CARDIOLOGIA
ISSN 0300-8932  Vol. 64  Nº 10  2011  págs. 947 - 948
Autores: Fortuño, Ana; Moreno, MU; et al.
Revista: JOURNAL OF HYPERTENSION
ISSN 0263-6352  Vol. 28  Nº 9  2010  págs. 1944 - 1950
Autores: García-Guerra, Lucía; Nieto-Vazquez, Iria; Vila-Bedmar, Rocío; et al.
Revista: DIABETES
ISSN 0012-1797  Vol. 59  Nº 10  2010  págs. 2407 - 2417
Autores: Moreno, MU; Beloqui, Óscar; et al.
Revista: JOURNAL OF HYPERTENSION
ISSN 0263-6352  Vol. 28  Nº 11  2010  págs. 2219 - 2226
Autores: Moreno, MU; Zalba, Guillermo;
Revista: DRUG NEWS AND PERSPECTIVES
ISSN 0214-0934  Vol. 23  Nº 5  2010  págs. 316 - 324
Oxidative stress plays a key rote in the pathophysiology of coronary artery disease, and constitutes a common mechanism behind the risk factors associated with this disease such as atherosclerosis, hypertension, diabetes and the metabolic syndrome. Oxidative stress is defined as an imbalance between the production of reactive oxygen and nitrogen species and the detoxification by the appropriate cellular systems. Reactive oxygen species induce cardiovascular dysfunction by modulating cell contraction/dilation, migration, growth/apoptosis and extracellular matrix protein turnover, which contribute to vascular and cardiac remodeling. In the last decade, the NADPH oxidase family has emerged as one of the most relevant sources of reactive oxygen species within the cardiovascular system. Recent data suggest a significant role of the genetic background in NADPH oxidase regulation. Common genetic polymorphisms within the promoter and exonic sequences of CYBA, the gene that encodes the p22(phox) subunit of the NADPH oxidase, have been characterized in the context of cardiovascular diseases. This review aims to present the current state of research into these polymorphisms with regards to their relationship to coronary artery disease.
Autores: Pejenaute, Álvaro; Zalba, Guillermo;
Libro:  Obesity: oxidative stress and dietary antioxidants
2018  págs. 93 - 110
Oxidative stress, a pathological situation created by an imbalance between reactive oxygen species production and antioxidant capacity, is a critical mechanism that underlies the pathophysiology of cardiovascular diseases and is involved in obesity, metabolic syndrome, and diabetes. The nicotinamide adenine dinucleotide phosphate (NADPH) oxidase enzyme family is the main source of reactive oxygen species and its expression and activity is enhanced and plays a critical role in the onset and/or development of cardiovascular diseases. The phagocytic NADPH oxidase, a member of the NADPH oxidase family present in lymphocytes, monocytes, and neutrophils, has been implicated in the pathophysiology of these vascular and metabolic disorders, by promoting detrimental prooxidant processes that could increase the morbidity and mortality in these diseases. A present challenge consists of the development of novel NADPH oxidase-selective drugs that could prevent and/or treat cardiovascular and metabolic diseases.
Autores: Pejenaute, Álvaro; Zalba, Guillermo;
Libro:  Telomeres, diet and human disease: advances and therapeutic opportunities
2018  págs. 39 - 54
Autores: Moreno, MU; Zalba, Guillermo;
Libro:  Oxidative Stress. A focus on cardiovascular disease pathogenesis
2010  págs. 95 - 109
Autores: Zalba, Guillermo; Díez, J;
Libro:  Studies on Cardiovascular Disorders
2010  págs. 169-186

ACTIVIDAD DOCENTE

   

Estructura y Función de biomoléculas (F.Ciencias). 
Universidad de Navarra - Facultad de Ciencias.

Introducción a la Tecnología del DNA recombinante (MIDI). 
Universidad de Navarra - Facultad de Ciencias.

Biotecnología Farmacéutica (F.Farmacia). 
Universidad de Navarra - Facultad de Ciencias.