Guillermo Zalba

Universidad de Navarra, Iruña, Navarre, Spain

Are you Guillermo Zalba?

Claim your profile

Publications (101)422.51 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: 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 (age ± SD: 67.0 ± 6.0 y, 45% males) from the PREDIMED-NAVARRA (PREvención con DIeta MEDiterránea-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 mor
    No preview · Article · Sep 2015 · American Journal of Clinical Nutrition
  • [Show abstract] [Hide abstract]
    ABSTRACT: The interaction between tumor necrosis factor-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. In this study we found that TWEAK and Fn14 are colocalized with the NADPH subunits, p22phox and Nox2, in advanced atherosclerotic plaques from humans. Using primary human macrophages and a murine macrophage cell line, we demonstrate that TWEAK promotes ROS production and enhances NADPH oxidase activity. Thus, we show that the TWEAK-Fn14 axis is involved directly, as genetic silencing of Fn14 abrogates the TWEAK-induced ROS production. Furthermore, our results point at Rac1 as an upstream mediator of TWEAK during oxidative stress. This is supported by the fact that genetic silencing Tnfsf12 in an ApoE (-/-) background reduces the number of DHE and 8-OHdG positive macrophages significantly. Our results suggest that TWEAK regulates vascular damage by stimulating ROS production in Nox2 dependent manner. These new insights into the TWEAK/Fn14 axis underline their potential use as therapeutic targets in atherosclerosis. Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2015. For permissions please email: journals.permissions@oup.com.
    No preview · Article · Jul 2015 · Cardiovascular Research
  • [Show abstract] [Hide abstract]
    ABSTRACT: To assess the potential association between TRX-1/PRX-1 and NADPH oxidase (Nox) activity in vivo and 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). This data was confirmed in a second study where 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, 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 NAPDH 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 exosomes-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. Copyright © 2015. Published by Elsevier Inc.
    No preview · Article · Jun 2015 · Free Radical Biology and Medicine
  • [Show abstract] [Hide abstract]
    ABSTRACT: -The gene variant Pro/Ala (rs1801282) in the PPARγ2 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. -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). -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 pattern strengthens the prevention of telomere shortening among Ala carriers. Clinical Trial Registration-www.controlled-trials.com; Unique Identifier: ISRCTN35739639.
    No preview · Article · Nov 2014 · Circulation Cardiovascular Genetics
  • [Show abstract] [Hide abstract]
    ABSTRACT: 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 (β=-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.
    No preview · Article · Aug 2014 · Clinical Nutrition
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: 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.
    Full-text · Article · Jun 2014 · Journal of the American Heart Association
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: 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. 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. 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). 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. 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. 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.
    Full-text · Article · Feb 2014 · PLoS ONE
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: 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.
    Preview · Article · Dec 2013 · Hypertension
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: 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.
    Full-text · Article · Jul 2013 · Journal of physiology and biochemistry
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: 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.International Journal of Obesity advance online publication, 28 May 2013; doi:10.1038/ijo.2013.68.
    Full-text · Article · May 2013 · International Journal of Obesity
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The NADPH oxidases are a key family of 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. We evaluated Nox4 expression and its relationship with myocardial remodelling and left ventricular function in patients with severe aortic valve stenosis (AS). Endomyocardial biopsies from 34 patients with AS were obtained during aortic valve replacement surgery. Left ventricular morphology and function were assessed by echocardiography. Myocardial samples from subjects deceased of non-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, vascular smooth muscle cells, endothelium and fibroblasts. Nox4 levels were 5-fold reduced 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 (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.
    Full-text · Article · Apr 2013 · Clinical Science
  • [Show abstract] [Hide abstract]
    ABSTRACT: 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.
    No preview · Article · Feb 2013 · Journal of Hypertension
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: 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-β₁ (TGF-β₁). We investigated whether a chronic treatment with P144, a peptide synthesized from type III TGF-β₁ 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-β₁-stimulated NRK52E exhibited a significant increase in NADPH oxidase expression and activity as well as a TGF-β₁-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-β₁-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-β₁-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.
    Full-text · Article · Jan 2013 · Antioxidants & Redox Signaling
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: 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.
    Full-text · Article · Aug 2012 · PLoS ONE
  • Source

    Full-text · Conference Paper · Aug 2012
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: NADPH oxidases constitute a major source of superoxide anion ( ⋅ O 2 - ) in hypertension. Several studies suggest an important role of NADPH oxidases in different effects mediated by TGF-β 1. In this study we show that chronic administration of P144, a peptide synthesized from type III TGF-β 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-β 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-β 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-β 1.
    Full-text · Article · Jun 2012 · Oxidative Medicine and Cellular Longevity
  • [Show abstract] [Hide abstract]
    ABSTRACT: 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-γ (PPARγ) agonists to reduce oxidative stress seems to contribute to their anti-inflammatory properties. This study analyzes the effect of pioglitazone, a PPARγ agonist, on interleukin-1β-induced COX-2 expression and the role of reactive oxygen species (ROS) on this effect. Vascular smooth muscle cells from hypertensive rats stimulated with interleukin-1β (10 ng/ml, 24 h) were used. Interleukin-1β 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 (IκB) kinase (IKK) nuclear expression of the p65 nuclear factor kappa B (NF-κB) subunit and cell proliferation, all of which were reduced by apocynin (30 μmol/l). Interleukin-1β-induced COX-2 expression was reduced by apocynin, tempol (10 μmol/l), catalase (1000 U/ml) and lactacystin (5 μmol/l). Moreover, H2O2 (50 μmol/l, 90 min) induced COX-2 expression, which was reduced by lactacystin. Pioglitazone (10 μmol/l) reduced the effects of interleukin-1β 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 H2O2-induced COX-2 expression and increased Cu/Zn and Mn-superoxide dismutase protein expression. PPARγ small interfering RNA (5 nmol/l) further increased interleukin-1β-induced COX-2 and NOX-1 mRNA levels. In addition, pioglitazone increased the interleukin-1β-induced PPARγ mRNA levels. PPARγ activation with pioglitazone reduces interleukin-1β-induced COX-2 expression by interference with the redox-sensitive transcription factor NF-κB.
    No preview · Article · Dec 2011 · Journal of Hypertension

  • No preview · Article · Nov 2011 · Free Radical Biology and Medicine
  • Manuel F. Landecho · Ana Fortuño · Guillermo Zalba · Oscar Beloqui

    No preview · Article · Oct 2011 · Revista Espa de Cardiologia
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: 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. 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-1α over-expression in co-transfection experiments and prevented by HIF-1α silencing. The direct interaction of HIF-1α 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. Hypoxia increased CT-1 levels in cardiac cells (in vitro and in vivo) through a direct regulation of CTF1 promoter by HIF-1α. 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.
    Full-text · Article · Aug 2011 · Cardiovascular Research

Publication Stats

2k Citations
422.51 Total Impact Points

Institutions

  • 1996-2015
    • Universidad de Navarra
      • • Division of Cardiovascular Sciences
      • • Department of Nutrition, Food Science and Physiology
      • • Department of Cardiology and Cardiovascular Surgery
      • • Department of Internal Medicine
      • • School of Medicine
      • • Department of Biochemistry and Molecular Biology
      Iruña, Navarre, Spain