Victoria Cachofeiro

Complutense University of Madrid, Madrid, Madrid, Spain

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Publications (155)441.16 Total impact

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    ABSTRACT: This study investigated whether galectin (Gal)-3 inhibition could block aldosterone-induced cardiac and renal fibrosis and improve cardiorenal dysfunction. Aldosterone is involved in cardiac and renal fibrosis that is associated with the development of cardiorenal injury. However, the mechanisms of these interactions remain unclear. Gal-3, a β-galactoside-binding lectin, is increased in heart failure and kidney injury. Rats were treated with aldosterone-salt combined with spironolactone (a mineralocorticoid receptor antagonist) or modified citrus pectin (a Gal-3 inhibitor), for 3 weeks. Wild-type and Gal-3 knockout mice were treated with aldosterone for 3 weeks. Hemodynamic, cardiac, and renal parameters were analyzed. Hypertensive aldosterone-salt-treated rats presented cardiac and renal hypertrophy (at morphometric, cellular, and molecular levels) and dysfunction. Cardiac and renal expressions of Gal-3 as well as levels of molecular markers attesting fibrosis were also augmented by aldosterone-salt treatment. Spironolactone or modified citrus pectin treatment reversed all of these effects. In wild-type mice, aldosterone did not alter blood pressure levels but increased cardiac and renal Gal-3 expression, fibrosis, and renal epithelial-mesenchymal transition. Gal-3 knockout mice were resistant to aldosterone effects. In experimental hyperaldosteronism, the increase in Gal-3 expression was associated with cardiac and renal fibrosis and dysfunction but was prevented by pharmacological inhibition (modified citrus pectin) or genetic disruption of Gal-3. These data suggest a key role for Gal-3 in cardiorenal remodeling and dysfunction induced by aldosterone. Gal-3 could be used as a new biotarget for specific pharmacological interventions. Copyright © 2014 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.
    JACC. Heart failure. 11/2014;
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    ABSTRACT: Background It has been reported that increased expression of UCP-2 in the vasculature may prevent the development of atherosclerosis in patients with increased production of reactive oxygen species, as in the diabetes, obesity or hypertension. Thus, a greater understanding in the modulation of UCP-2 could improve the atherosclerotic process. However, the effect of TNF-¿ or insulin modulating UCP-2 in the vascular wall is completely unknown. In this context, we propose to study new molecular mechanisms that help to explain whether the moderate hyperinsulinemia or lowering TNF-¿ levels might have a protective role against vascular damage mediated by UCP-2 expression levels.Methods We analyzed the effect of insulin or oleic acid in presence or not of TNF-¿ on UCP-2 expression in murine endothelial and vascular smooth muscle cells. At this step, we wondered if some mechanisms studied in vitro could be of any relevance in vivo. We used the following experimental models: ApoE¿/¿ mice under Western type diet for 2, 6, 12 or 18 weeks, BATIRKO mice under high-fat diet for 16 weeks and 52-week-old BATIRKO mice with o without anti-TNF-¿ antibody pre-treatment.ResultsFirstly, we found that TNF-¿ pre-treatment reduced UCP-2 expression induced by insulin in vascular cells. Secondly, we observed a progressive reduction of UCP-2 levels together with an increase of lipid depots and lesion area in aorta from ApoE¿/¿ mice. In vivo, we also observed that moderate hyperinsulinemic obese BATIRKO mice have lower TNF-¿ and ROS levels and increased UCP-2 expression levels within the aorta, lower lipid accumulation, vascular dysfunction and macrovascular damage. We also observed that the anti-TNF-¿ antibody pre-treatment impaired the loss of UCP-2 expression within the aorta and relieved vascular damage observed in 52-week-old BATIRKO mice. Finally, we observed that the pretreatment with iNOS inhibitor prevented UCP-2 reduction induced by TNF-¿ in vascular cells. Moreover, iNOS levels are augmented in aorta from mice with lower UCP-2 levels and higher TNF-¿ levels.Conclusions Our data suggest that moderate hyperinsulinemia in response to insulin resistance or lowering of TNF-¿ levels within the aorta attenuates vascular damage, this protective effect being mediated by UCP-2 expression levels through iNOS.
    Cardiovascular Diabetology 07/2014; 13(1):108. · 4.21 Impact Factor
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    ABSTRACT: We have previously reported that leptin can participate in the cardiovascular fibrosis associated with obesity. One of the key steps in the synthesis and maturation of the ECM involves the enzyme lysyl oxidase (LOX), which allows the crosslinking of collagen and elastin fibers and the formation of a stable and insoluble ECM. Therefore, we explore the effects of an inhibitor of LOX activity, beta-aminopropionitrile (BAPN), on cardiovascular alterations in a model of diet-induced obesity in rats, and whether or not these effects could involve the modulation of the profibrotic effects of leptin.
    Cardiovascular research. 07/2014; 103(suppl 1):S88.
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    ABSTRACT: Leptin acts as a cardiac profibrotic factor. However, the mechanisms underlying this effect are unclear. Therefore, we sought to elucidate the mediators involved in this process and the potential role of leptin in cardiac fibrosis associated with obesity. Male Wistar rats were fed either a high-fat diet (HFD; 33.5% fat), or a standard diet (3.5% fat) for 6 weeks. HFD animals show cardiac hypertrophy, fibrosis and an increase in O2 production as evaluated by dihydroethidium. Echocardiographic parameters of cardiac structure and systolic function were similar in both groups. Cardiac levels of leptin, collagen I, galectin-3 and transforming growth factor β (TGF-β) were higher in HFD than in controls. In cardiac myofibroblasts, leptin (10-100 ng/ml) increased O2, collagen I, galectin-3, TGF-β and connective tissue growth factor production (CTGF). These effects were prevented by the presence of either melatonin (10 mmol/l) or the inhibitor of mTOR, rapamycin (10 mmol/l). Blockage of galectin-3 activity by N-acetyllactosamine (LacNac 10 mmol/l) reduced both collagen I and O2 production induced by leptin. The p70S6 kinase activation/phosphorylation, the downstream mediator of mTOR, induced by leptin was not modified by melatonin. Leptin reduced the metalloproteinase (MMP) 2 activity and the presence of melatonin, rapamycin or LacNac were unable to prevent it. The data suggest that leptin locally produced in the heart could participate in the fibrosis observed in HFD by affecting collagen turnover. Collagen synthesis induced by leptin seems to be mediated by the production of galectin-3, TGF-β and CTGF through oxidative stress increased by activation of mTOR pathway.
    Journal of Hypertension 05/2014; 32(5):1104-14. · 4.22 Impact Factor
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    ABSTRACT: Myocarditis and dilated cardiomyopathy (DCM) are inflammatory diseases of the myocardium, for which appropriate treatment remains a major clinical challenge. Oleanolic acid (OA), a natural triterpene widely distributed in food and medicinal plants, possesses a large range of biological effects with beneficial properties for health and disease prevention. Several experimental approaches have shown its cardioprotective actions, and OA has recently been proven effective for treating Th1 cell-mediated inflammatory diseases; however, its effect on inflammatory heart disorders, including myocarditis, has not yet been addressed. Therefore, the present study was undertaken to determine the effectiveness of OA in prevention and treatment of experimental autoimmune myocarditis (EAM). The utility of OA was evaluated in vivo through their administration to cardiac α-myosin (MyHc-α614-629)-immunized BALB/c mice from day 0 or day 21 post-immunization to the end of the experiment, and in vitro through their addition to stimulated-cardiac cells. Prophylactic and therapeutic administration of OA dramatically decreased disease severity: the heart weight/body weight ratio as well as plasma levels of brain natriuretic peptide and myosin-specific autoantibodies production were significantly reduced in OA-treated EAM animals, compared with untreated ones. Histological heart analysis showed that OA-treatment diminished cell infiltration, fibrosis and dystrophic calcifications. OA also decreased proliferation of cardiac fibroblast in vitro and attenuated calcium and collagen deposition induced by relevant cytokines of active myocarditis. Furthermore, in OA-treated EAM mice the number of Treg cells and the production of IL-10 and IL-35 were markedly increased, while proinflammatory and profibrotic cytokines were significantly reduced. We demonstrate that OA ameliorates both developing and established EAM by promoting an antiinflammatory cytokine profile and by interfering with the generation of cardiac-specific autoantibodies, as well as through direct protective effects on cardiac cells. Therefore, we envision this natural product as novel helpful tool for intervention in inflammatory cardiomyopathies including myocarditis.
    Journal of Molecular and Cellular Cardiology 04/2014; · 5.15 Impact Factor
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    ABSTRACT: Abstract Obesity and excess of adipose tissue are associated with the development of cardiovascular risk factors such as diabetes, hypertension, and hyperlipidemia. At the cardiac level, various morphological adaptations in cardiac structure and function occur in obese individuals. Different mechanisms linking obesity to these modifications have been postulated. Adipose tissue and epicardial fat releases a large number of cytokines and bioactive mediators such as leptin. Leptin circulates in proportion to body fat mass, thus serving as a satiety signal and informing central metabolic control centers as to the status of peripheral energy stores. It participates in numerous other functions both peripherally and centrally, as indicated by the wide distribution of leptin and the different isoforms of its receptor in different tissues including the heart. This hormone has distinct effects on the reproductive, cardiovascular, and immune systems; however, its role in the heart could mediate wide physiological effects observed in obese individuals. Oxidative stress is associated with obesity and may be considered to be a unifying mechanism in the development of obesity-related comorbidities. It has been reported that obesity may induce systemic oxidative stress; in turn, oxidative stress is associated with an irregular production of adipokines. We herein review the current knowledge of cardiac effects of leptin and the possible mechanisms that are involved, including oxidative stress that plays a major role in the development of cardiovascular damage.
    Hormone molecular biology and clinical investigation 04/2014; 18(1):3-14.
  • Victoria Cachofeiro, Vicente Lahera
    Hormone molecular biology and clinical investigation 04/2014; 18(1-3):1-2.
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    ABSTRACT: To study the effects of rosuvastatin on insulin resistance in overweight rats induced by high fat diet, as well as potential mediators. We used male Wistar rats fed with a standard diet (CT) or high fat diet (33.5% fat) (HFD); half of the animals HFD were treated with rosuvastatin (15mg/kg/day) (HFD+Rosu) for 7 weeks. HFD rats showed increased body, epididymal and lumbar adipose tissue weights. Treatment with Rosu did not modify body weight or the weight of the adipose packages in HFD rat. Plasma glucose and insulin levels and HOMA index were higher in HFD rats, and rosuvastatin treatment reduced them. Leptin/adiponectin ratio in plasma and lumbar adipose tissue were higher in HDF rats, and were reduced by rosuvastatin. SIRT-1, PPAR-γ and GLUT-4 protein expression in lumbar adipose tissue were lower in HFD rats and Rosu normalized expression of the three mediators. Rosuvastatin ameliorates insulin sensitivity induced by HFD in rats. This effect is mediated by several mechanisms including reduction of leptin and enhancement of SIRT-1, PPAR-γ and GLUT-4 expression in white adipose tissue. SIRT1 could be considered a major mediator of the beneficial effects of rosuvastatin on insulin sensitivity in overweight rats induced by diet.
    Clinica e Investigacion en Arteriosclerosis 03/2014;
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    ABSTRACT: Background/Objectives:Extracellular matrix (ECM) participates in the vascular remodeling associated with obesity. We investigated the effects of leptin on the production of ECM components in primary cultured vascular smooth muscle cells (VSMCs) and whether leptin could be a mediator of obesity-induced vascular remodeling.Methods:The effects of leptin (100 ng/ml) on ECM components and superoxide anion production (O2(.-)) were evaluated in presence or absence of the antioxidant melatonin (10(-3) mmol/L) or the inhibitor of PI3K, LY294002 (2 × 10(-4) mmol/L) in VSMCs from adult rats in order to explore the role of both oxidative stress and the participation of PI3K/Akt pathway in the effects of leptin. ECM components and O2(.-) were quantified in the aortic media of male Wistar rats fed a high-fat diet (HFD; 33.5% fat), or a standard diet (CT; 3.5% fat) for 6 weeks.Results:In VSMCs, leptin enhanced gene and protein levels of collagen I, fibronectin, TGF-β, CTGF but did not change those of collagen III and galectin-3. Leptin also increased O2(.-) and Akt phosphorilation in VSMCs. These effects were prevented by the presence of either melatonin or LY294002, except the O2(.-) production in the case of PI3K inhibition. The increase in body weight in HFD rats was accompanied by aorta thickening due to an increase in media area. The aortic fibrosis observed in HFD rats was associated with high levels of leptin, collagen type I, fibronectin, TGF-β, CTGF, phosphorylated Akt and O2(.-). Aortic leptin levels were positively correlated with total collagen, collagen I, TGF-β and CTGF levels. No differences were observed in levels of collagen III, elastin or galectin-3 between both groups.Conclusions:Leptin could participate in the vascular remodeling and stiffness associated with obesity by ECM production in VSMCs through the activation of oxidative stress-PI3K/Akt pathway and the production of the profibrotic factors TGF-β and CTGF.International Journal of Obesity accepted article preview online, 3 March 2014; doi:10.1038/ijo.2014.37.
    International journal of obesity (2005) 03/2014; · 5.22 Impact Factor
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    ABSTRACT: Background Myocarditis and dilated cardiomyopathy (DCM) are inflammatory diseases of the myocardium, for which appropriate treatment remains a major clinical challenge. Oleanolic acid (OA), a natural triterpene widely distributed in food and medicinal plants, possesses a large range of biological effects with beneficial properties for health and disease prevention. Several experimental approaches have shown its cardioprotective actions, and OA has recently been proven effective for treating Th1 cell-mediated inflammatory diseases; however, its effect on inflammatory heart disorders, including myocarditis, has not yet been addressed. Therefore, the present study was undertaken to determine the effectiveness of OA in prevention and treatment of experimental autoimmune myocarditis (EAM). Methods The utility of OA was evaluated in vivo through their administration to cardiac α-myosin (MyHc-α614 -629)-immunized BALB/c mice from day 0 or day 21 post-immunization to the end of the experiment, and in vitro through their addition to stimulated-cardiac cells. Results Prophylactic and therapeutic administration of OA dramatically decreased disease severity: the heart weight/body weight ratio as well as plasma levels of brain natriuretic peptide and myosin-specific autoantibodies production were significantly reduced in OA-treated EAM animals, compared with untreated ones. Histological heart analysis showed that OA-treatment diminished cell infiltration, fibrosis and dystrophic calcifications. OA also decreased proliferation of cardiac fibroblast in vitro and attenuated calcium and collagen deposition induced by relevant cytokines of active myocarditis. Furthermore, in OA-treated EAM mice the number of Treg cells and the production of IL-10 and IL-35 were markedly increased, while proinflammatory and profibrotic cytokines were significantly reduced. Conclusions We demonstrate that OA ameliorates both developing and established EAM by promoting an antiinflammatory cytokine profile and by interfering with the generation of cardiac-specific autoantibodies, as well as through direct protective effects on cardiac cells. Therefore, we envision this natural product as novel helpful tool for intervention in inflammatory cardiomyopathies including myocarditis.
    Journal of Molecular and Cellular Cardiology 01/2014; · 5.15 Impact Factor
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    ABSTRACT: Objective To study the effects of rosuvastatin on insulin resistance in overweight rats induced by high fat diet, as well as potential mediators. Methods We used male Wistar rats fed with a standard diet (CT) or high fat diet (33.5% fat) (HFD); half of the animals HFD were treated with rosuvastatin (15 mg/kg/day) (HFD + Rosu) for 7 weeks. Results HFD rats showed increased body, epididymal and lumbar adipose tissue weights. Treatment with Rosu did not modify body weight or the weight of the adipose packages in HFD rat. Plasma glucose and insulin levels and HOMA index were higher in HFD rats, and rosuvastatin treatment reduced them. Leptin/adiponectin ratio in plasma and lumbar adipose tissue were higher in HDF rats, and were reduced by rosuvastatin. SIRT-1, PPAR-γ and GLUT-4 protein expression in lumbar adipose tissue were lower in HFD rats and Rosu normalized expression of the three mediators. Conclusions Rosuvastatin ameliorates insulin sensitivity induced by HFD in rats. This effect is mediated by several mechanisms including reduction of leptin and enhancement of SIRT-1, PPAR-γ and GLUT-4 expression in white adipose tissue. SIRT1 could be considered a major mediator of the beneficial effects of rosuvastatin on insulin sensitivity in overweight rats induced by diet.
    Clínica e Investigación en Arteriosclerosis. 01/2014;
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    ABSTRACT: Las estatinas han demostrado claramente su capacidad para disminuir la morbimortalidad cardiovascular debido principalmente a sus efectos sobre el colesterol sérico y las LDL, además de la estabilización de la placa y la reducción del riesgo trombótico. Sin embargo, en los últimos años diversos estudios indican que las estatinas tienen además efectos sobre la PA y la protección de órganos diana. Estos efectos pueden ser en parte dependientes de la reducción de la colesterolemia, pero otros mecanismos distintos a éste parecen intervenir en los efectos antihipertensivos de las estatinas. Entre ellos sus acciones sobre el manejo renal de sodio, la respuesta constrictora a diversos agentes, el remodelado vascular y diversas acciones sobre factores vasoactivos derivados del endotelio y el sistema renina angiotensina.
    Hipertensión y Riesgo Vascular. 07/2013; 17(8):357–364.
  • Hipertensión y Riesgo Vascular 07/2013; 17(1):22–29.
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    ABSTRACT: Mercury exposure is known to increase cardiovascular risk but the underlying cellular mechanisms remain undetermined. We analyzed whether chronic exposure to HgCl2 affects vascular structure and the functional properties of vascular smooth muscle cells (VSMC) through oxidative stress/cyclooxygenase-2 dependent pathways. Mesenteric resistance arteries and aortas from Wistar rats treated with HgCl2 (first dose 4.6 mg kg− 1, subsequent doses 0.07 mg kg− 1 day− 1, 30 days) and cultured aortic VSMC stimulated with HgCl2 (0.05–5 μg/ml) were used. Treatment of rats with HgCl2 decreased wall thickness of the resistance and conductance vasculature, increased the number of SMC within the media and decreased SMC nucleus size. In VSMCs, exposure to HgCl2: 1) induced a proliferative response and a reduction in cell size; 2) increased superoxide anion production, NADPH oxidase activity, gene and/or protein levels of the NADPH oxidase subunit NOX-1, the EC- and Mn-superoxide dismutases and cyclooxygenase-2 (COX-2); 3) induced activation of ERK1/2 and p38 MAPK. Both antioxidants and COX-2 inhibitors normalized the proliferative response and the altered cell size induced by HgCl2. Blockade of ERK1/2 and p38 signaling pathways abolished the HgCl2-induced Nox1 and COX-2 expression and normalized the alterations induced by mercury in cell proliferation and size. In conclusion, long exposure of VSMC to low doses of mercury activates MAPK signaling pathways that result in activation of inflammatory proteins such as NADPH oxidase and COX-2 that in turn induce proliferation of VSMC and changes in cell size. These findings offer further evidence that mercury might be considered an environmental risk factor for cardiovascular disease.
    Toxicology and Applied Pharmacology 04/2013; 268(2):188–200. · 3.98 Impact Factor
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    ABSTRACT: BACKGROUND AND AIM: To investigate whether rosuvastatin can improve insulin sensitivity in overweight rats having a high fat diet (HFD). The potential mechanisms involved in this action were evaluated, including SIRT-1, other factors involved in glucose metabolism and stress signaling pathways. METHODS AND RESULTS: Male Wistar rats (n = 30) were divided into three groups: (i) rats fed a standard diet (3.5% fat); (ii) rats fed a HFD (33.5% fat); and (iii) rats fed a HFD and treated with rosuvastatin (15 mg/kg/day). Evolution: 7 weeks. HFD rats showed increased body, epididymal and lumbar adipose tissue weights. Plasma levels of cholesterol, triglycerides, VLDL, glucose and insulin and leptin/adiponectin ratio were higher in HFD rats, and rosuvastatin treatment reduced them. SIRT-1, p53, PGC-1α, PPAR-γ and GLUT-4 protein levels in white adipose tissue (WAT) were lower, and JNK was higher in HFD rats compared to controls. Rosuvastatin treatment normalized expression of these mediators. Endothelium-dependent relaxation was reduced in mesenteric rings from HFD rats compared to controls and rosuvastatin enhanced it in HFD rats. CONCLUSION: Rosuvastatin treatment reduced insulin resistance without affecting body weight or WAT loss in HFD rats. Reduction of leptin and JNK, and enhancement of SIRT-1, p53, PGC-1α, PPAR-γ and GLUT-4 expression in WAT could contribute to insulin sensitization. Normalization of SIRT-1 expression in WAT could be considered a key novel mechanism that aids in explaining the beneficial effects of rosuvastatin on the amelioration of glucose metabolism and the arrangement of multiple signaling pathways participating in insulin resistance in overweight HFD rats.
    Nutrition, metabolism, and cardiovascular diseases: NMCD 02/2013; · 3.52 Impact Factor
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    ABSTRACT: The function of the Interleukin-33 (IL-33)/ST2 system has been mainly investigated on immunological aspects, but recent data suggest that this pathway plays also an important role in cardiovascular system and adipose tissue. Whereas IL-33 has been demonstrated to exert anti-inflammatory and protective effects, circulating soluble ST2 (sST2) has emerged as a prognostic biomarker in patients with myocardial infarction and heart failure. Furthermore, sST2 is increased in severe obesity, although its role in the pathogenesis of vascular remodeling associated with obesity is still not well defined. Male Wistar rats fed standard diet (Control) or high fat diet (HFD) for 6 weeks. Aortic tunica media from diet-induced obese animals showed hypertrophy and fibrosis. The IL-33/ST2 system was spontaneously expressed in the aorta from Wistar rats. Administration of HFD in animals did not modify IL-33 expression at the transcriptional level. By contrast, HFD group showed an increase in aortic soluble sST2 and a decrease in the transmembrane isoform (ST2L) levels, resulting in decreased protective pathway activity. Aortic sST2 mRNA levels were associated with parameters showing vascular hypertrophy and fibrosis. In vitro experiments showed that primary cultured vascular smooth muscle cells (VSMCs) spontaneously expressed the IL-33/ST2 system. VSMCs stimulated with sST2 showed an increase in collagen type I, fibronectin and profibrotic factors. This is the first study demonstrating a deleterious role for sST2 in the vascular remodeling associated with obesity. In addition, we demonstrated that sST2 may act not only as a decoy receptor by binding IL-33 and preventing ST2L, but also modulating ECM remodeling and turnover. Thus, sST2 could be a new therapeutic target to reduce vascular remodeling in the context of obesity.
    PLoS ONE 01/2013; 8(11):e79176. · 3.53 Impact Factor
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    ABSTRACT: The mechanisms involved in cardiac remodeling in left (LV) and right ventricles (RV) after myocardial infarction (MI) are still unclear. We assayed factors involved in collagen turnover in both ventricles following MI in rats either presenting signs of heart failure (pulmonary congestion and increased LVEDP) or not (INF-HF or INF, respectively). MI was induced in male rats by ligation of the left coronary artery. Four weeks after MI gene expression of collagen I, connective tissue growth factor (CTGF), transforming growth factor β (TGF-β) and lysyl oxidase (LOX), metalloproteinase-2 (MMP2) and tissue inhibitor metalloproteinase-2 (TIMP2) as well as cardiac hemodynamic in both ventricles were evaluated. Ventricular dilatation, hypertrophy and an increase in interstitial fibrosis and myocyte size were observed in the RV and LV from INF-HF animals, whereas only LV dilatation and fibrosis in RV was present in INF. The LV fibrosis in INF-HF was associated with higher mRNA of collagen I, CTGF, TGF-β and LOX expressions than in INF and SHAM animals, while MMP2/TIMP2 mRNA ratio did not change. RV fibrosis in INF and INF-HF groups was associated with an increase in LOX mRNA and a reduction in MMP2/TIMP2 ratio. CTGF mRNA was increased only in the INF-HF group. INF and INF-HF animals presented different patterns of remodeling in both ventricles. In the INF-HF group, fibrosis seems to be consequence of collagen production in LV, and by reductions in collagen degradation in RV of both INF and INF-HF animals.
    PLoS ONE 01/2013; 8(5):e64986. · 3.53 Impact Factor
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    ABSTRACT: New Findings• What is the central question of this study? Does PGC‐1α play a key role in vascular alterations induced by cholesterol+coconut oil diet in rabbits? • What is the main finding and its importance? Vascular expression of PGC‐1α, SIRT1 and PPARγ were reduced in atherosclerotic rabbits. Furthermore, PGC‐1α correlated with processes involved in atherosclerosis (endothelial dysfunction, oxidative stress and inflammation). Reduction of PGC‐1α seems to play an important role in the molecular alterations during the development of atherosclerosis. Peroxisome proliferator‐activated receptor γ coactivator‐1α (PGC‐1α) is emerging as a novel factor that plays a critical role in integrating signalling pathways in the control of cellular and systemic metabolism. We investigated the role of vascular expression of PGC‐1α and related factors, such as sirtuin 1 (SIRT1), peroxisome proliferator‐activated receptor γ (PPARγ) and adiponectin, during the atherosclerotic process. Endothelial function, vascular superoxide anion production and inflammatory mediators were also evaluated. This study was carried out in male New Zealand rabbits fed a diet containing 0.5% cholesterol and 14% coconut oil for 8 weeks. Animals developed mixed dyslipidaemia and atherosclerotic lesions, which were associated with endothelial dysfunction, aortic overproduction of superoxide anions and inflammation. Expression of PGC‐1α, SIRT1, PPARγ and adiponectin was reduced (P P P Document Type: Research Article DOI: http://dx.doi.org/10.1113/expphysiol.2012.070557 Affiliations: 1: Department of Physiology, School of Medicine, Universidad Complutense, Madrid, Spain 2: Department of Physiology, School of Medicine, Universidad Autónoma, Madrid, Spain Publication date: May 1, 2013 $(document).ready(function() { var shortdescription = $(".originaldescription").text().replace(/\\&/g, '&').replace(/\\, '<').replace(/\\>/g, '>').replace(/\\t/g, ' ').replace(/\\n/g, ''); if (shortdescription.length > 350){ shortdescription = "" + shortdescription.substring(0,250) + "... more"; } $(".descriptionitem").prepend(shortdescription); $(".shortdescription a").click(function() { $(".shortdescription").hide(); $(".originaldescription").slideDown(); return false; }); }); Related content In this: publication By this: publisher In this Subject: Anatomy & Physiology By this author: Valero‐Muñoz, M. ; Martín‐Fernández, B. ; Ballesteros, S. ; Martínez‐Martínez, E. ; Blanco‐Rivero, J. ; Balfagón, G. ; Cachofeiro, V. ; Lahera, V. ; de las Heras, N. GA_googleFillSlot("Horizontal_banner_bottom");
    Experimental Physiology 01/2013; 98(5). · 2.79 Impact Factor
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    ABSTRACT: BACKGROUND AND PURPOSE: Regular physical activity is an effective non-pharmacological therapy for prevention and control of hypertension. We investigated the effects of aerobic exercise training in vascular remodeling and in the mechanical and functional alterations of coronary and small mesenteric arteries from spontaneously hypertensive rats (SHR). EXPERIMENTAL APPROACH: Normotensive Wistar Kyoto (WKY), SHR and SHR-Trained rats (treadmill, 12 weeks) were used to evaluate vascular structural, mechanical and functional properties. KEY RESULTS: Exercise did not affect lumen diameter, wall thickness and wall/lumen ratio, but reduced vascular stiffness of coronary and mesenteric arteries from SHR. Exercise also reduced collagen deposition and normalized altered internal elastic lamina organization and matrix metalloproteinase 9 expression in mesenteric arteries from SHR. Exercise did not affect contractile responses of coronary arteries but improved the endothelium-dependent relaxation in SHR. In mesenteric arteries, training normalized the increased contractile responses induced by U46619 and by high concentrations of acetylcholine. In vessels from SHR, exercise: 1) normalized the effects of the NADPH oxidase inhibitor apocynin and the NOS inhibitor L-NAME in vasodilator or vasoconstrictor responses; 2) normalized the increased O(2) (.-) production and the reduced Cu/Zn superoxide dismutase expression and 3) increased NO production. CONCLUSIONS AND IMPLICATIONS: Exercise training of SHR improves endothelial function and vascular stiffness in coronary and small mesenteric arteries. This might be related with the concomitant decrease of oxidative stress and the increase of NO bioavailability. These events might contribute to reduce blood pressure and provide evidences of the beneficial effects of exercise on the vascular system.
    British Journal of Pharmacology 09/2012; · 5.07 Impact Factor
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    ABSTRACT: Ezetimibe, a selective inhibitor of intestinal cholesterol absorption, effectively reduces plasma cholesterol both in monotherapy or combined with a statin. However, its effect on atherosclerosis plaque progression is certainly unknown. MicroRNAs are short non-encoding RNA molecules dynamically implicated in monocytic differentiation which is considered an essential process during atherosclerosis development. The purpose of this study was to investigate the effect of ezetimibe on monocyte/macrophage differentiation as well as the implication of microRNAs (miRNAs) in this process. THP-1 differentiation with PMA became cells adherent to the plastic surface, and induced the expression of macrophage surface markers (CD11a, CD11b and ICAM-1) and miR-155, miR-222, miR-424 and miR-503. In the presence of ezetimibe, the adhesive capacity of THP-1 cells was decreased in a dose-dependent manner (P<0.05) and the expression of CD11a, CD11b and ICAM-1 was almost totally inhibited (P<0.05). The expression of miR-155, miR-222, miR-424 and miR-503 was reduced by 55%, 100%, 75% and 100%, respectively (P<0.05). Further mechanistic studies demonstrated that ezetimibe suppressed the PMA-induced phosphorylation of ERK/MAPK and inhibited the NF-κB activity, which are upstream signalling molecules in the differentiation process. In conclusion, ezetimibe inhibits PMA-induced THP-1 cell differentiation into macrophage-like cells in association with the inhibition of miRNA pathways. Our study suggests that inhibition of miRNAs might form a novel mechanism of anti-atherosclerotic effect of ezetimibe.
    Pharmacological Research 09/2012; · 4.35 Impact Factor

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1k Citations
441.16 Total Impact Points

Institutions

  • 1988–2014
    • Complutense University of Madrid
      • • Department of Physiology
      • • Departamento de Medicina
      • • Departamento de Radiología y Medicina Física (Radiología)
      Madrid, Madrid, Spain
  • 2013
    • Universidade Federal do Espírito Santo
      • Departamento de Ciências Fisiológicas
      Victoria, Espírito Santo, Brazil
  • 2012
    • Hospital Clínico Universitario de Valladolid
      Valladolid, Castille and León, Spain
    • Université Paris-Sud 11
      Orsay, Île-de-France, France
  • 2011
    • University of São Paulo
      • Departamento de Fisiologia e Biofísica (ICB)
      Ribeirão Preto, Estado de Sao Paulo, Brazil
  • 2010
    • Universidad de Sevilla
      • Instituto de Biomedicina de Sevilla (IBIS)
      Sevilla, Andalusia, Spain
    • Centro de Investigaciones Biológicas
      Madrid, Madrid, Spain
  • 2009
    • Fundación Cardiovascular de Colombia
      Florida, Santander, Colombia
  • 2007
    • Hospital General Universitario Gregorio Marañón
      Madrid, Madrid, Spain
  • 2004
    • Universidad Autónoma de Madrid
      • Departamento de Fisiología
      Madrid, Madrid, Spain
  • 2002
    • Universidad Nacional Autónoma de México
      Ciudad de México, The Federal District, Mexico
  • 2000
    • Hospital Clínico San Carlos
      Madrid, Madrid, Spain
  • 1999
    • Novartis
      Bâle, Basel-City, Switzerland
  • 1991–1997
    • New York Medical College
      • Department of Pharmacology
      New York City, NY, United States
  • 1996
    • University of Murcia
      • Facultad de Medicina
      Murcia, Murcia, Spain