Person:
Zamorano León, José Javier

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First Name
José Javier
Last Name
Zamorano León
Affiliation
Universidad Complutense de Madrid
Faculty / Institute
Medicina
Department
Salud Pública y Materno-Infantil
Area
Medicina Preventiva y Salud Pública
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Now showing 1 - 10 of 17
  • Publication
    Platelet Content of Nitric Oxide Synthase 3 Phosphorylated At Serine1177 Is Associated with the Functional Response of Platelets to Aspirin
    (Public Library of Science, 2013-10-24) Modrego, Javier; Azcona, Luis; Martín Palacios, Naiara; Zamorano León, José Javier; Segura, Antonio; Rodriguez, Pablo; Guerra, Reddy; Tamargo Menéndez, Juan; Macaya Miguel, Carlos; López Farre, Antonio José
    Objective: To analyse if platelet responsiveness to aspirin (ASA) may be associated with a different ability of platelets to generate nitric oxide (NO). Patients/methods: Platelets were obtained from 50 patients with stable coronary ischemia and were divided into ASA-sensitive (n = 26) and ASA-resistant (n = 24) using a platelet functionality test (PFA-100). Results: ASA-sensitive platelets tended to release more NO (determined as nitrite + nitrate) than ASA-resistant platelets but it did not reach statistical significance. Protein expression of nitric oxide synthase 3 (NOS3) was higher in ASA-sensitive than in ASA-resistant platelets but there were no differences in the platelet expression of nitric oxide synthase 2 (NOS2) isoform. The highest NOS3 expression in ASA-sensitive platelets was independent of the presence of T-to-C mutation at nucleotide position -786 (T(-786) → C) in the NOS3-coding gene. However, platelet content of phosphorylated NOS3 at Serine (Ser)(1177), an active form of NOS3, was higher in ASA-sensitive than in ASA-resistant platelets. The level of platelet NOS3 Ser(1177) phosphorylation was positively associated with the closure time in the PFA-100 test. In vitro, collagen failed to stimulate the aggregation of ASA-sensitive platelets, determined by lumiaggregometry, and it was associated with a significant increase (p = 0.018) of NOS3 phosphorylation at Ser(1177). On the contrary, collagen stimulated the aggregation of ASA-resistant platelets but did not significantly modify the platelet content of phosphorylated NOS3 Ser(1177). During collagen stimulation the release of NO from ASA-sensitive platelets was significantly enhanced but it was not modified in ASA-resistant platelets. Conclusions: Functional platelet responsiveness to ASA was associated with the platelet content of phosphorylated NOS3 at Ser(1177).
  • Publication
    A Proteomic Approach to Determine Changes in Proteins Involved in the Myocardial Metabolism in Left Ventricles of Spontaneously Hypertensive Rats
    (S. Karger AG, 2010-07-01) Zamorano León, José Javier; Modrego, Javier; Mateos Cáceres, Petra; Macaya Miguel, Carlos; Martín Fernández, Beatriz; Miana, María; Heras Jiménez, Natalia De Las; Cachofeiro Ramos, María Victoria; Lahera Julia, Vicente; López Farre, Antonio José
    Different works have suggested that in the hypertrophied heart the energy metabolic pathway shifts to glycolysis. Our aim was to evaluate using proteomics the expression of proteins associated with different energetic metabolic pathways in hypertrophied left ventricles of spontaneously hypertensive rats (SHR). Methods: 24-weeks-old SHR with stable hypertension and established left ventricle hypertrophy were used. Normotensive Wistar Kyoto rats were used as control. Proteins from left ventricles were analyzed by 2-dimensional electrophoresis and identified by comparison with a virtual rat heart proteomic map and mass spectrometry. Results: Enoyl-CoA hydratase expression, an enzyme involved in fatty acid β-oxidation, was reduced whereas the expression of other β-oxidation enzymes, 3-ketoacyl-CoA thiolase and the mitochondrial precursor of acyl-CoA thioester hydrolase, was increased in the hypertrophied left ventricles. The expression of two enzymes involved in the first steps of glycolysis, fructose bisphosphate aldolase and triosephosphate isomerase, was reduced in the left ventricle of SHR. Pyruvate dehydrogenase expression, enzyme involved in glucose oxidation, was enhanced in the hypertrophied ventricles whereas proteins of the tricarboxylic acid cycle were not modified. Proteins involved in the mitochondrial oxidative phosphorylation were overexpressed whereas the α-subunit of the mitochondrial precursor of ATP synthase was downexpressed. Conclusions: Several proteins involved in the main energy metabolic pathways were up and downexpressed. Moreover, our results seem to suggest that probably neither fatty acid β-oxidation nor glycolysis are the only sources for energy in the hypertrophied left ventricle.
  • Publication
    Plasma desmoplakin I biomarker of vascular recurrence after ischemic stroke
    (Wiley, 2012-07-01) López Farre, Antonio José; Zamorano León, José Javier; Segura, Antonio; Jiménez Mateos Cáceres, Petra; Modrego, Javier; Rodriguez Sierra, Pablo; Calatrava, Laura; Tamargo Menéndez, Juan; Macaya Miguel, Carlos
    Stroke patients have a high risk of vascular recurrence. Biomarkers related to vascular recurrence, however, remain to be identified. The aim of the study was to identify, through proteomic analysis, plasma biomarkers associated with vascular recurrence within one year after the first ischemic stroke. This is a substudy (n = 134) of a large prospective multicenter study of post-stroke patients with an ischemic stroke. Plasma samples were obtained at inclusion. Among the identified proteins, only plasma levels of desmoplakin I were associated with protection against a new vascular event (Odds ratio: 0.64; 95% CI: 0.46-0.89; p = 0.009) after adjustment for hypercholesterolemia, statins and previous atherothrombotic stroke subtype. A greater number of patients without vascular recurrence had been treated with statins within three months of the recent ischemic stroke. Only patients who had been taking statins for 3 months after the ischemic stroke and did not suffer vascular recurrence over a follow-up year, have higher levels of desmoplakin I at the time of inclusion (Odds ratio 0.49; 95% CI: 0.28-0.86; p = 0.013). Increased desmoplakin I levels, determined within 1-3 months of the first ischemic stroke, could be a biomarker for statin responsiveness against a new vascular event in post-ischemic stroke patients taking statins early (1-3 months) after the ischemic stroke.
  • Publication
    Escitalopram Impairs Thrombin-Induced Platelet Response, Cytoskeletal Assembly and Activation of Associated Signalling Pathways
    (Thieme Gruppe, 2017-07-01) López Víchez, Irene; Jerez Dolz, Didac; Díaz Ricart, Maribel; Navarro, Víctor; Urooj Zafar, M; Zamorano León, José Javier; López Farre, Antonio José; Badimon, Juan; Gasto, Cristóbal; Escolar, Ginés
    Background Serotonin reuptake inhibitors (SSRIs) may impair platelet function. Thrombin is a strong platelet agonist causing irreversible aggregation, release of granules' contents, cytoskeletal rearrangement and activation of signalling pathways. We investigated the effects of the SSRI escitalopram (SCIT) on thrombin-induced platelet response. Methods Isolated platelets were exposed to SCIT and activated with thrombin. We evaluated (1) platelet response by aggregometry and flow cytometry; (2) modifications in cytoskeleton proteins and signalling pathways by electrophoresis and Western blot; and (3) ultrastructural changes in platelets by electron microscopy. Results SCIT inhibited platelet response to thrombin, measured as platelet aggregation and expression of activation markers CD62-P and CD63 from platelet granules. Platelet aggregation decreased in a dose-dependent manner, reaching statistical significance with SCIT ≥32 µg/mL (65.4 ± 6.8% vs. 77.7 ± 2.5% for controls; p < 0.05). Expression of activation markers was statistically reduced with SCIT ≥20 µg/mL (p < 0.05). SCIT impaired the polymerization of the actin cytoskeleton and association of contractile proteins during activation with thrombin (p < 0.05 with SCIT ≥50 µg/mL). Resting platelets incubated with SCIT became most spherical, with increased platelet roundness (p < 0.01, SCIT 50 µg/mL vs. control). SCIT interfered with signalling pathways modulated by thrombin (RhoA, PKC, Erk1/2 and PI3K/AKT). Conclusions Our data indicate that SCIT inhibits thrombin-induced platelet response and interferes with cytoskeletal assembly and related signalling pathways, thus resulting in compromised release of granules' contents, reduced platelet activation and aggregation. These mechanisms may explain the antithrombotic benefits observed in patients treated with this SSRI, and could become new therapeutic targets for future antithrombotic strategies.
  • Publication
    Impact of Clopidogrel and Aspirin Treatment on the Expression of Proteins in Platelets from Type-2 Diabetic Patients with Stable Coronary Ischemia
    (Elsevier, 2012-07-01) Azcona, Luis; López Farre, Antonio José; Jiménez Mateos Cáceres, Petra; Segura, Antonio; Rodríguez Sierra, Pablo; Modrego, Javier; Zamorano León, José Javier; Macaya Miguel, Carlos
    The purpose of this study was to compare the effect of dual antiplatelet therapy [clopidogrel + aspirin (ASA)] with respect to ASA on the protein expression of platelets from controlled type-2 diabetic patients with stable coronary ischemia. Patients had been taking ASA (100 mg day) and they were randomized to receive (n = 29) or not (n = 28) 75 mg day clopidogrel for 12 ± 2 weeks in a blind form. Protein expression was analyzed by two-dimensional electrophoresis and mass spectrometry. The protein expression of a limited number of proteins such as actin-binding protein isotypes 2 and 5, lactate dehydrogenase, serotransferrin isotype 4, protein disulfide isomerase-A3 isotype 1, fibrinogen beta chain isotype 5, Ras-related protein Rab-7b isotypes 1 and 6, and immunoglobulin heavy chain was changed after dual antiplatelet therapy. Plasma level of platelet factor 4 (PF4), an in vivo marker of platelet activity, was not different between both groups. These changes suggest lower platelet reactivity after dual antiplatelet therapy in the studied patients. However, the variation in platelet proteome was lower than it would be initially expected, taking into account the apparent clinical beneficial effects of dual antiplatelet therapy. PF4 plasma level was not further decreased in the platelets treated for a longer time than 9-12 months with ASA + clopidogrel, as compared with ASA alone.
  • Publication
    Nitric oxide from mononuclear cells may be involved in platelet responsiveness to aspirin
    (Wiley, 2014-07-01) López Farre, Antonio José; Modrego Javier; Azcona, Luis; Guerra, Redy; Segura, Antonio; Rodríguez Sierra, Pablo; Zamorano León, José Javier; Lahera Julia, Vicente; Macaya Miguel, Carlos
    Background Several mechanisms have been proposed to explain why some platelets have a reduced response to aspirin (ASA). Among them, it was reported an increased circulating level of vitamin-D-binding protein (DBP). In addition, nitric oxide (NO) released from mononuclear cells was involved in the antiplatelet effects of ASA. The aim was to analyse the relationship between platelet response to ASA and both NO generation and vitamin-D-binding protein content in mononuclear cells. Materials and methods Mononuclear cells were obtained from patients with stable coronary artery disease that were divided by a platelet functionality test (PFA-100) as ASA-sensitive (n = 23) and ASA resistant (n = 27). Results Both the release of NO (determined by nitrite + nitrate concentration) and the expression of endothelial-type NO synthase (eNOS) were higher in mononuclear cells from ASA sensitive as compared with those from ASA-resistant patients. There was a positive correlation between either the release of NO and the expression of eNOS protein in mononuclear cells with the ability of ASA to inhibit platelet activity. DBP content in mononuclear cells was higher in ASA resistant than in ASA sensitive. The level of DBP content in mononuclear cells was negatively associated with the ability of ASA to inhibit platelets. However, in vitro experiments suggested that there was no association between DBP and NO production by mononuclear cells. Conclusions Mononuclear cells from patients with platelets with lower responsiveness to ASA showed a reduced ability to produce NO.
  • Publication
    Síndrome de tako-tsubo e insuficiencia cardiaca: seguimiento a largo plazo
    (Sociedad Española de Cardiología, 2012-11-01) Núñez Gil, Iván Javier; Alonso, Joaquín; Zamorano León, José Javier; Macaya Miguel, Carlos; Fernández Ortiz, Antonio Ignacio
    Introduction and objectives: Tako-tsubo syndrome produces a variable degree of transient left ventricular dysfunction. Our objective was to determine the short- and long-term prognosis of this syndrome, the incidence of and risk factors for the development of heart failure, and the influence on heart failure on the long-term outcome in our patient population. Methods: We prospectively recorded the clinical features and events during the hospital stay and follow-up of 100 patients with tako-tsubo syndrome. The risk factors for heart failure during hospital stay, considered as Killip class≥II, were assessed. Results: Most of the patients were women (89%), with a mean age of 68 years. The distribution according to Killip class was: Killip I, 70 patients; Killip II, 15; Killip III, 5; and Killip IV, 10. Cardiovascular risk factors, including diabetes, were common in the overall group, but were more so in the heart failure cohort. The left ventricular ejection fraction was lower in the heart failure group (51% vs 42%; P<.01). There were no differences in preadmission medications or biomarkers of necrosis. Over a median follow-up of 1380 days, the incidence of events reported during the hospital stay and long-term follow-up, both for death and the combined endpoints, was higher in the heart failure cohort. Conclusions: Although the prognosis in tako-tsubo syndrome is usually good, heart failure occurs quite frequently, mainly in patients with a greater number of comorbidities and poorer previous functional class. Moreover, heart failure is associated with a higher number of early and late adverse events. The overall long-term prognosis is good.
  • Publication
    Vardenafil Improves Penile Erection in Type 2 Diabetes Mellitus Patients with Erectile Dysfunction: Role of Tropomyosin
    (Elsevier, 2013-07-01) Zamorano León, José Javier; Olivier, Carlos; Heras Jiménez, Natalia De Las; Mateos Cáceres, Petra; Rodríguez Sierra, Pablo; Martín Palacios, Naihara; Modrego, Javier; Macaya Miguel, Carlos; López Farre, Antonio José
    Introduction. Evidences have been suggested that phosphodiesterase type 5 (PDE5) inhibition promotes vasculoprotective benefits in patients with cardiovascular diseases. Aim. The aim of this study is to analyze the systemic effect of PDE5 inhibition in type 2 diabetes mellitus patients with erectile dysfunction (ED) determining changes in the expression levels of plasma proteins. Methods. Seventeen patients with controlled type 2 diabetes mellitus and ED were included in the study. Patients received vardenafil hydrochloride 20 mg on demand during 12 weeks. At the beginning and 12 weeks after vardenafil administration, plasma samples were collected and analyzed using proteomics. Main Outcome Measures. International Index of Erectile Function-Erectile Function Domain (IIEF-EFD) and plasma protein expression before and after vardenafil administration. Nitrate/nitrite release, PDE5, and soluble guanylate cyclase (sGC) expression and cyclic guanosine monophosphate (cGMP) content in cultured bovine aortic endothelial cells (BAECs). Results. The IIEF-EFD score was markedly improved after 12 weeks of vardenafil administration. Plasma levels of alpha 1-antitrypsin isotypes 4 and 6 and β-tropomyosin were decreased, whereas apolipoprotein AI isoype 5 was increased 12 weeks after vardenafil administration. Only β-tropomyosin plasma levels were inversely correlated with IIEF-EFD score. Tropomyosin has been added to cultured BAECs and after 24 hours reduced the protein expression level of sGC-β1 subunit and decreased the cGMP content. Tropomyosin did not modify PDE5 expression and nitric oxide release in BAECs as compared with control BAECs. Vardenafil (10 μg/mL) did not modify sGC-β1 subunit expression in tropomyosin + vardenafil-incubated BAECs; however, vardenafil significantly reversed the reduction of cGMP content induced by tropomyosin. Conclusion. Vardenafil administration improved erectile functionality in controlled type 2 diabetes mellitus patients with ED, which was associated with reduction of circulating plasma β-tropomyosin levels. Tropomyosin affected by itself the cGMP generating system suggesting a possible new mechanism involved in ED. Vardenafil reversed the reduction effect of cGMP content elicited by tropomyosin in BAECs. Zamorano-León JJ, Olivier C, de las Heras N, Mateos-Cáceres PJ, Brime Menéndez R,Rodríguez-Sierra P, Martín Palacios N, Manso LSJ, Modrego J, Segura A, Macaya C, and López-Farré AJ. Vardenafil improves penile erection in type 2 diabetes mellitus patients with erectile dysfunction: Role of tropomyosin. J Sex Med 2013;10:3110–3120.
  • Publication
    Endothelial damage in major depression patients is modulated by SSRI treatment, as demonstrated by circulating biomarkers and an in vitro cell model
    (Springer Nature, 2016-07-01) Lopez Vilchez, Irene; Diaz Ricart, M; Navarro, V; Zamorano León, José Javier; López Farre, Antonio José; Galán, A. M.; Gasto C; Escolar G
    There is a link between depression, cardiovascular events and inflammation. We have explored this connection through endothelial dysfunction, using in vivo and in vitro approaches. We evaluated circulating biomarkers of endothelial dysfunction in patients with major depression at their diagnosis (MD-0) and during antidepressant treatment with the selective serotonin reuptake inhibitor escitalopram, for 8 and 24 weeks (MD-8 and MD-24). Results were always compared with matched healthy controls (CON). We measured in vivo circulating endothelial cells (CECs) and endothelial progenitor cells (EPCs) in blood samples, and assessed plasma levels of soluble von Willebrand factor (VWF) and vascular cell adhesion molecule-1 (VCAM-1). CEC counts, soluble VWF and VCAM-1 were statistically elevated in MD-0 (P<0.01 versus CON) and gradually decreased during treatment. Conversely, EPC levels were lower in MD-0, tending to increase throughout treatment. In vitro studies were performed in human endothelial cells cultured in the presence of sera from each study group. Elevated expression of the inflammation marker intercellular adhesion molecule-1 and oxidative stress, with lower presence of endothelial nitric oxide synthase and higher reactive oxygen species production, were found in cells exposed to MD-0 sera (P<0.05 versus CON). These results were normalized in cells exposed to MD-24 sera. Thrombogenicity of extracellular matrices generated by these cells, measured as expression of VWF, tissue factor and platelet reactivity, showed non-significant differences. We provide a model of cultured endothelial cells reproducing endothelial dysfunction in naive patients with major depression, demonstrating endothelial damage and inflammation at diagnosis, and recovering with selective serotonin reuptake inhibitor treatment for 24 weeks.
  • Publication
    Serum biomarkers in uncontrolled no heart-beating donors may identify kidneys that will never work after transplantation
    (Springer, 2016-07-01) López Farre, Antonio José; Santos Sancho, Juana María; Modrego, Javier; Zamorano León, José Javier; Martín, Leyre; Sánchez Fructuoso, Ana Isabel; Rodríguez Sierra, Pablo; Herrero Calvo, José Antonio; Río Gallegos, Francisco José Del; Barrientos Alberto; Barrientos Guzmán, Alberto
    Background/aims Kidneys from uncontrolled non heart-beating donors achieve a good level of renal function after transplantation. However, a number of them will never function in the recipient. Our aim was to determine if serum biomarkers associated with platelet activity, inflammation and the nitric oxide system in uncontrolled non heart-beating donors may help to predict no renal function recovery after renal transplantation. Methods Serum levels of interleukin (IL)-6, IL-10, intercellular cell adhesion molecule-1 (ICAM-1), cyclic guanosine monophosphate (cGMP), nitrite + nitrate and platelet factor-4 (PF4) were measured using enzyme-linked immunosorbent assay (ELISA) kits in 88 uncontrolled non heart-beating donors divided according to the renal functionality achieved in the recipients into functional (n = 76) and non functional (n = 12). Results Kidneys from donors with higher IL-6 levels (>900 pg/ml) were functional after transplantation. Serum cGMP levels below 372.3 fmol/l were also associated with kidneys that recovered the renal function. However, serum levels of PF4 showed the best correlation with recovery of renal functional in the recipients since they were significantly lower in the donors whose kidneys functioned after transplantation. Conclusions Serum PF4 levels in uncontrolled non heart-beating donors may be a good predictor for kidneys that never will reach functional recovery. Some serum cGMP, IL-6 and IL-10 levels may simply help identify kidneys that will function after transplantation.