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
Identifiers
17 results
Search Results
Now showing 1 - 10 of 17
Item Escitalopram Impairs Thrombin-Induced Platelet Response, Cytoskeletal Assembly and Activation of Associated Signalling Pathways(Thrombosis and Haemostasis, 2017) 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, GinésBackground 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.Item Platelet Content of Nitric Oxide Synthase 3 Phosphorylated At Serine1177 Is Associated with the Functional Response of Platelets to Aspirin(PLoS ONE, 2013) 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 JoséObjective: 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).Item Vardenafil Improves Penile Erection in Type 2 Diabetes Mellitus Patients with Erectile Dysfunction: Role of Tropomyosin(The Journal of Sexual Medicine, 2013) 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 JoséIntroduction. 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.Item Endothelial damage in major depression patients is modulated by SSRI treatment, as demonstrated by circulating biomarkers and an in vitro cell model(Transl Psychiatry, 2016) Lopez Vilchez, Irene; Diaz Ricart, M; Navarro, V; Zamorano León, José Javier; López Farre, Antonio José; Galán, A. M.; Gasto C; Escolar GThere 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.Item Serum biomarkers in uncontrolled no heart-beating donors may identify kidneys that will never work after transplantation(Journal of Nephrology, 2016) 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, AlbertoBackground/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.Item Changes in cardiac energy metabolic pathways in overweighed rats fed a high-fat diet(European Journal of Nutrition, 2013) Modrego, Javier; Heras Jiménez, Natalia De Las; Zamorano León, José Javier; Mateos Cáceres, Petra; Martín Fernández, Beatriz; Valero Muñoz, María; Lahera Julia, Vicente; López Farré, VicenteBackground: Heart produces ATP through long-chain fatty acids beta oxidation. Purpose: To analyze whether in ventricular myocardium, high-fat diet may modify the expression of proteins associated with energy metabolism before myocardial function was affected. Methods: Wistar Kyoto rats were divided into two groups: (a) rats fed standard diet (control; n = 6) and (b) rats fed high-fat diet (HFD; n = 6). Proteins from left ventricles were analyzed by two-dimensional electrophoresis, mass spectrometry and Western blotting. Results: Rats fed with HFD showed higher body weight, insulin, glucose, leptin and total cholesterol plasma levels as compared with those fed with standard diet. However, myocardial functional parameters were not different between them. The protein expression of 3-ketoacyl-CoA thiolase, acyl-CoA hydrolase mitochondrial precursor and enoyl-CoA hydratase, three long-chain fatty acid β-oxidation-related enzymes, and carnitine-O-palmitoyltransferase I was significantly higher in left ventricles from HFD rats. Protein expression of triosephosphate isomerase was higher in left ventricles from HFD rats than in those from control. Two α/β-enolase isotypes and glyceraldehyde-3-phosphate isomerase were significantly increased in HFD rats as compared with control. Pyruvate and lactate contents were similar in HFD and control groups. Expression of proteins associated with Krebs cycle and mitochondrial oxidative phosphorylation was higher in HFD rats. Conclusions: Expression of proteins involved in left ventricle metabolic energy was enhanced before myocardial functionality was affected in rats fed with HFD. These findings may probably indicate higher cardiac energy requirement due to weight increase by HFD.Item BRCA2 gene mutations and coagulation-associated biomarkers(Thrombosis and Haemostasis, 2015) Pérez Segura, Pedro; Zamorano León, José Javier; Acosta, Daniel; Santos Sancho, Juana María; Modrego, Javier; Caldés, Trinidad; de la Hoya, Miguel; Díaz-Rubio García, Eduardo; Díaz Millán, Isabel; Heras Jiménez, Natalia De Las; Rico Zalba, Luis; Lahera Julia, Vicente; Melander, Olle; López Farre, Antonio JoséThromboembolic events are the second cause of death in cancer patients, although the mechanisms underlying this increased thromboembolic risk remain unclear. The aims of this study were to examine whether BRCA2 gene mutations may modify the circulating levels of thrombocoagulation biomarkers and whether breast cancer development may influence changes in such circulating biomarkers. The study was performed in 25 women with mutations in the BRCA2 gene (n=12 breast cancer, n=13 breast cancer-free) and in 13 BRCA2 non-mutant controls. Results revealed that plasma levels of fibrinogen gamma chain isotypes 2 and 3, haptoglobin isotypes 4 and 5, serotransferrin isotypes 3 and 4 and convertase C3/C5 isotypes 4 and 5 were significantly higher in BRCA2 mutation carriers compared to controls. However, plasma levels of vitamin D binding protein isotype 1 and alpha1-antitrypsin isotypes 2, 3 and 4 were significantly decreased in BRCA2 mutation carriers compared to controls. Plasma expression of PF4 and P-selectin was significantly higher in BRCA2 mutations carriers than in controls. BRCA2 truncated mutations conserving a binding region for RAD51 were associated with increased plasma levels of alpha1-antitrypsin isotypes 3 and 4 with respect to women showing BRCA2 mutations that loss the binding RD51 region to BRCA2. Only plasma levels of vitamin D binding protein isotypes 1 and 3 were significantly reduced and alpha 1-antitrypsin isotype 1 was increased in cancer-free BRCA2 mutation carriers compared to BRCA2 mutation carriers with breast cancer. The presence of BRCA2 mutations is associated with increased plasma levels of thrombo-coagulating-related proteins, which are independent to breast cancer development.Item FXa inhibition by rivaroxaban modifies mechanisms associated with the pathogenesis of human abdominal aortic aneurysms(British Journal of Clinical Pharmacology, 2017) Moñux Ducaju, Guillermo; Zamorano León, José Javier; Marqués Pablo; Sopeña, Bernardo; García García, José Manuel; Laich de Koller, Guillermo; Calvo Rico, Bibiana; García Fernández, Miguel Ángel; Serrano, Javier; López Farre, Antonio JoséAims To evaluate if rivaroxaban, an oral factor Xa (FXa) inhibitor, could modify the expression in vitro of inflammatory and oxidative stress biomarkers in abdominal aortic aneurysmal (AAA) sites showing intraluminal thrombus. Methods AAA sites with intraluminal mural thrombus were obtained from six patients undergoing elective AAA repair. In addition, control abdominal aortic samples were obtained from six organ donors. AAA sites were incubated in the presence and absence of 50 nmol l–1 rivaroxaban. Results AAA sites showing thrombus demonstrated higher content of FXa than control. Interleukin-6 levels released from AAA [Control: median: 23.45 (interquartile range: 16.17–37.15) vs. AAA: median: 153.07 (interquartile range: 100.80–210.69) pg ml–1 mg tissue–1, P < 0.05] and the expression levels of nitric oxide synthase 2 were significantly higher in AAA than in control. The protein expression level of NADPH oxidase subunits gp67-and gp91-phox, but did not gp47-phox, were also significantly higher in the AAA sites than in control. Addition of rivaroxaban to AAA sites explants significantly reduced the release of interleukin-6 [median: 51.61 (interquartile range: 30.87–74.03) pg ml–1 mg tissue–1, P < 0.05 with respect to AAA alone] and the content of nitric oxide synthase 2, gp67 and gp91-phox NADPH subunits. The content of matrix metallopeptidase 9 was significantly higher in the AAA sites as compared to control. Rivaroxaban also reduced matrix metallopeptidase 9 content in AAA sites to similar levels to control. Conclusions FXa inhibition by rivaroxaban exerted anti-inflammatory and antioxidative stress properties in human AAA sites, suggesting a role of FXa in these mechanisms associated with the pathogenesis of AAA.Item Trends in mechanical ventilation use and mortality over time in patients receiving mechanical ventilation in Spain from 2001 to 2015.(European Journal of Internal Medicine, 2019) Miguel Díez, Javier De; Jiménez García, Rodrigo; Hernández Barrera, Valentín; Zamorano León, José Javier; Villanueva Orbaiz, M. Rosa Rita; Albaladejo Vicente, Romana; López De Andrés, Ana Isabel; ElsevierBackground: We examined trends in the incidence of ventilator support with noninvasive ventilation (NIV) or invasive mechanical ventilation (IMV) among patients hospitalized in Spain from 2001 to 2015. We also assessed in-hospital mortality (IHM) after receiving these types of ventilator support. Methods: This study was an observational retrospective epidemiological study. Our data source was the Spanish National Hospital Discharge Database. Results: In total, 1,031,497 patients received ventilator support in Spain over the study period. NIV use increased from 18.8 patients per 100.000 inhabitants in 2001 to 108.7 in 2015. IMV utilization increased significantly from 2001 to 2003 and then decreased from 2003 until 2015. Patients who required NIV had the highest mean Charlson Comorbidity Index (CCI) score. Patients who received IMV had the highest in-hospital mortality. Factors associated with an increased risk for IHM were sex, age, conditions included in the CCI (except for COPD and diabetes), haemodialysis, presence of a peripheral arterial catheter, presence of a central venous catheter, readmission and emergency room admission. Undergoing a surgical procedure was a risk factor only for IMV. IHM decreased significantly from 2001 to 2015 in patients who underwent NIV or IMV. Conclusions: We identified an increase in the utilization of NIV over time, whereas use of IMV decreased from 2003 until 2015 after an initial increase from 2001 to 2003. We also found a significant decrease in IHM over time.Item Plasma desmoplakin I biomarker of vascular recurrence after ischemic stroke(Journal of Neurochemistry, 2012) 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, CarlosStroke 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.