Person: Zaragoza, Carlos
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Carlos
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Zaragoza
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CNIC
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Publication CIBER-CLAP (CIBERCV Cardioprotection Large Animal Platform): A multicenter preclinical network for testing reproducibility in cardiovascular interventions.(2019-12-30) Rossello, Xavier; Rodriguez-Sinovas, Antonio; Vilahur, Gemma; Crisóstomo, Verónica; Jorge, Inmaculada; Zaragoza, Carlos; Zamorano, José L; Bermejo, Javier; Ordoñez, Antonio; Boscá, Lisardo; Vázquez, Jesús; Badimón, Lina; Sánchez-Margallo, Francisco M; Fernández-Avilés, Francisco; Garcia-Dorado, DavidDespite many cardioprotective interventions have shown to protect the heart against ischemia/reperfusion injury in the experimental setting, only few of them have succeeded in translating their findings into positive proof-of-concept clinical trials. Controversial and inconsistent experimental and clinical evidence supports the urgency of a disruptive paradigm shift for testing cardioprotective therapies. There is a need to evaluate experimental reproducibility before stepping into the clinical arena. The CIBERCV (acronym for Spanish network-center for cardiovascular biomedical research) has set up the "Cardioprotection Large Animal Platform" (CIBER-CLAP) to perform experimental studies testing the efficacy and reproducibility of promising cardioprotective interventions based on a pre-specified design and protocols, randomization, blinding assessment and other robust methodological features. Our first randomized, control-group, open-label blinded endpoint experimental trial assessing local ischemic preconditioning (IPC) in a pig model of acute myocardial infarction (n = 87) will be carried out in three separate sets of experiments performed in parallel by three laboratories. Each set aims to assess: (A) CMR-based outcomes; (B) histopathological-based outcomes; and (C) protein-based outcomes. Three core labs will assess outcomes in a blinded fashion (CMR imaging, histopathology and proteomics) and 2 methodological core labs will conduct the randomization and statistical analysis.Publication Specialized Proresolving Mediators Protect Against Experimental Autoimmune Myocarditis by Modulating Ca2+ Handling and NRF2 Activation.(Elsevier, 2022-06) Val-Blasco, Almudena; Prieto, Patricia; Jaén, Rafael Iñigo; Gil-Fernández, Marta; Pajares, Marta; Domenech, Nieves; Terrón, Verónica; Tamayo, María; Jorge, Inmaculada; Vazquez, Jesus; Bueno-Sen, Andrea; Vallejo-Cremades, María Teresa; Pombo-Otero, Jorge; Sanchez-García, Sergio; Ruiz-Hurtado, Gema; Gómez, Ana María; Zaragoza, Carlos; Crespo-Leiro, María Generosa; López-Collazo, Eduardo; Cuadrado, Antonio; Delgado, Carmen; Boscá, Lisardo; Fernández-Velasco, María; Ministerio de Economía y Competitividad (España); Unión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF); Instituto de Salud Carlos III; Sociedad Española de Cardiología; Unión Europea. Fondo Social Europeo (ESF/FSE); Centro de Investigación Biomédica en Red - CIBERCV (Enfermedades Cardiovasculares); Ministerio de Ciencia, Innovación y Universidades (España); Fundación La CaixaSpecialized proresolving mediators and, in particular, 5(S), (6)R, 7-trihydroxyheptanoic acid methyl ester (BML-111) emerge as new therapeutic tools to prevent cardiac dysfunction and deleterious cardiac damage associated with myocarditis progression. The cardioprotective role of BML-111 is mainly caused by the prevention of increased oxidative stress and nuclear factor erythroid-derived 2-like 2 (NRF2) down-regulation induced by myocarditis. At the molecular level, BML-111 activates NRF2 signaling, which prevents sarcoplasmic reticulum-adenosine triphosphatase 2A down-regulation and Ca2+ mishandling, and attenuates the cardiac dysfunction and tissue damage induced by myocarditis.Publication Non-Invasive Detection of Extracellular Matrix Metalloproteinase Inducer EMMPRIN, a New Therapeutic Target against Atherosclerosis, Inhibited by Endothelial Nitric Oxide(Multidisciplinary Digital Publishing Institute (MDPI), 2018) Ramirez-Carracedo, Rafael; Tesoro, Laura; Hernandez, Ignacio; Diez-Mata, Javier; Filice, Marco; Toro, Rocio; Rodriguez-Pinero, Manuel; Luis Zamorano, Jose; Saura, Marta; Zaragoza, Carlos; Instituto de Salud Carlos III; Comunidad de Madrid (España); Complutense University of Madrid (España); Francisco de Vitoria University (España); Unión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF)Lack of endothelial nitric oxide causes endothelial dysfunction and circulating monocyte infiltration, contributing to systemic atheroma plaque formation in arterial territories. Among the different inflammatory products, macrophage-derived foam cells and smooth muscle cells synthesize matrix metalloproteinases (MMPs), playing a pivotal role in early plaque formation and enlargement. We found increased levels of MMP-9 and MMP-13 in human endarterectomies with advanced atherosclerosis, together with significant amounts of extracellular matrix (ECM) metalloproteinase inducer EMMPRIN. To test whether the absence of NO may aggravate atherosclerosis through EMMPRIN activation, double NOS3/apoE knockout (KO) mice expressed high levels of EMMPRIN in carotid plaques, suggesting that targeting extracellular matrix degradation may represent a new mechanism by which endothelial NO prevents atherosclerosis. Based on our previous experience, by using gadolinium-enriched paramagnetic fluorescence micellar nanoparticles conjugated with AP9 (NAP9), an EMMPRIN-specific binding peptide, magnetic resonance sequences allowed non-invasive visualization of carotid EMMPRIN in NOS3/apoE over apoE control mice, in which atheroma plaques were significantly reduced. Taken together, these results point to EMMPRIN as a new therapeutic target of NO-mediated protection against atherosclerosis, and NAP9 as a non-invasive molecular tool to target atherosclerosis.Publication Beneficial effect of TLR4 blockade by a specific aptamer antagonist after acute myocardial infarction.(Elsevier, 2023-02) Paz-García, Marta; Povo-Retana, Adrián; Jaén, Rafael I; Prieto, Patricia; Peraza, Diego A; Zaragoza, Carlos; Hernandez-Jimenez, Macarena; Pineiro, David; Regadera, Javier; García-Bermejo, María L; Rodríguez-Serrano, E Macarena; Sánchez-García, Sergio; Moro, María A; Lizasoaín, Ignacio; Delgado, Carmen; Valenzuela, Carmen; Boscá, Lisardo; Ministerio de Ciencia, Innovación y Universidades (España); Agencia Estatal de Investigación (España); Centro de Investigación Biomédica en Red - CIBERCV (Enfermedades Cardiovasculares); Instituto de Salud Carlos III; Comunidad de Madrid (España); Fondation LeducqExperimental evidence indicates that the control of the inflammatory response after myocardial infarction is a key strategy to reduce cardiac injury. Cellular damage after blood flow restoration in the heart promotes sterile inflammation through the release of molecules that activate pattern recognition receptors, among which TLR4 is the most prominent. Transient regulation of TLR4 activity has been considered one of the potential therapeutic interventions with greater projection towards the clinic. In this regard, the characterization of an aptamer (4FT) that acts as a selective antagonist for human TLR4 has been investigated in isolated macrophages from different species and in a rat model of cardiac ischemia/reperfusion (I/R). The binding kinetics and biological responses of murine and human macrophages treated with 4FT show great affinity and significant inhibition of TLR4 signaling including the NF-κB pathway and the LPS-dependent increase in the plasma membrane currents (Kv currents). In the rat model of I/R, administration of 4FT following reoxygenation shows amelioration of cardiac injury function and markers, a process that is significantly enhanced when the second dose of 4FT is administered 24 h after reperfusion of the heart. Parameters such as cardiac injury biomarkers, infiltration of circulating inflammatory cells, and the expression of genes associated with the inflammatory onset are significantly reduced. In addition, the expression of anti-inflammatory genes, such as IL-10, and pro-resolution molecules, such as resolvin D1 are enhanced after 4FT administration. These results indicate that targeting TLR4 with 4FT offers new therapeutic opportunities to prevent cardiac dysfunction after infarction.Publication Cbfa-1 mediates nitric oxide regulation of MMP-13 in osteoblasts.(The Company of Biologists, 2006-05-01) Zaragoza, Carlos; Lopez-Rivera, Esther; Garcia-Rama, Concepcion; Saura, Marta; Martinez-Ruiz, Antonio; Lizarbe, Tania R; Martín-de-Lara, Fernando; Lamas, Santiago; Ministerio de Ciencia y Tecnología (España); Ministerio de Educación y Ciencia (España); Unión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF); Comunidad de Madrid (España); Sociedad Española de Nefrología; Centro de Investigación Biomédica en Red - CIBERCV (Enfermedades Cardiovasculares); Ministerio de Sanidad y Consumo (España)During bone development, osteoblast differentiation requires remodeling of the extracellular matrix. Although underlying mechanisms have not been elucidated, evidence points to the participation of the nitric oxide (NO) and cyclic guanosine 3',5'-monophosphate (cGMP) system. Here, we detected increased matrix metalloproteinase (MMP)-13 mRNA, protein and activity, as well as increased inducible NO synthase (iNOS) and NO production during the differentiation of MC3T3-E1 osteoblasts. Transcriptional activity of the MMP-13 promoter was augmented by NO, 8-bromo-cGMP (8-Br-cGMP), and by a dominant-positive form of protein kinase G (PKG1-alpha). The stimulatory effect on the MMP-13 promoter was partially inhibited by mutation of the osteoblast-specific element 2 (OSE-2) binding site. Core binding factor-1 (Cbfa-1) expression peaked at 7 days of differentiation, and was phosphorylated by PKG in vitro. Cbfa-1 was localized to cell nuclei, and its translocation was inhibited by the iNOS inhibitor 1400W. Immunohistological examination revealed that MMP-13 and Cbfa-1 expression levels are both reduced in 17-day-old embryos of iNOS-deficient mice. Silencing of Cbfa-1 mRNA blocked MMP-13 expression without interfering with endogenous NO production, confirming its role in NO-induced MMP-13 expression by MC3T3-E1 cells. The results described here suggest a mechanism by which NO regulates osteogenesis.Publication CIBER-CLAP (CIBERCV Cardioprotection Large Animal Platform): A multicenter preclinical network for testing reproducibility in cardiovascular interventions(Nature Publishing Group, 2019-12-30) Rossello, Xavier; Rodriguez-Sinovas, Antonio; Vilahur, Gemma; Crisóstomo, Verónica; Jorge, Inmaculada; Zaragoza, Carlos; Zamorano, José L; Bermejo, Javier; Ordoñez, Antonio; Boscá, Lisardo; Vazquez, Jesus; Badimón, Lina; Sánchez-Margallo, Francisco Miguel; Fernández-Avilés, Francisco; Garcia-Dorado, David; Ibáñez, Borja; Instituto de Salud Carlos III; Ministerio de Ciencia, Innovación y Universidades (España)Despite many cardioprotective interventions have shown to protect the heart against ischemia/reperfusion injury in the experimental setting, only few of them have succeeded in translating their findings into positive proof-of-concept clinical trials. Controversial and inconsistent experimental and clinical evidence supports the urgency of a disruptive paradigm shift for testing cardioprotective therapies. There is a need to evaluate experimental reproducibility before stepping into the clinical arena. The CIBERCV (acronym for Spanish network-center for cardiovascular biomedical research) has set up the "Cardioprotection Large Animal Platform" (CIBER-CLAP) to perform experimental studies testing the efficacy and reproducibility of promising cardioprotective interventions based on a pre-specified design and protocols, randomization, blinding assessment and other robust methodological features. Our first randomized, control-group, open-label blinded endpoint experimental trial assessing local ischemic preconditioning (IPC) in a pig model of acute myocardial infarction (n = 87) will be carried out in three separate sets of experiments performed in parallel by three laboratories. Each set aims to assess: (A) CMR-based outcomes; (B) histopathological-based outcomes; and (C) protein-based outcomes. Three core labs will assess outcomes in a blinded fashion (CMR imaging, histopathology and proteomics) and 2 methodological core labs will conduct the randomization and statistical analysis.Publication Animal models of atherosclerosis(Elsevier, 2012) Fuster, Jose J.; Castillo, Ana I; Zaragoza, Carlos; Ibáñez, Borja; Andres, Vicente; Ministerio de Ciencia e Innovación (España); Instituto de Salud Carlos III; Fundación ProCNICCardiovascular disease is currently the predominant cause of mortality worldwide and its incidence is expected to increase significantly during the next decades owing to the unhealthy effects of modern lifestyle habits (e.g., obesity and lack of physical exercise). Cardiovascular death is frequently associated with acute myocardial infarction or stroke, which are generally the ultimate consequence of an underlying atherosclerotic process. Small and big animal models are valuable tools to understand the molecular mechanisms underlying atherosclerotic plaque formation and progression, as well as the occurrence of associated ischemic events. Moreover, animal models of atherosclerosis are pivotal for testing mechanistic hypothesis and for translational research, including the assessment of dietary and/or pharmacological interventions and the development of imaging technologies and interventional devices. In this chapter, we will describe the most widely used animal models that have permitted major advances in atherosclerosis research and significant improvements in the treatment and diagnosis of atherosclerotic disease.Publication NIL10: A New IL10-Receptor Binding Nanoparticle That Induces Cardiac Protection in Mice and Pigs Subjected to Acute Myocardial Infarction through STAT3/NF-κB Activation.(Multidisciplinary Digital Publishing Institute (MDPI), 2022-09-26) Tesoro, Laura; Hernández, Ignacio; Ramírez-Carracedo, Rafael; Díez-Mata, Javier; Alcharani, Nunzio; Jiménez-Guirado, Beatriz; Ovejero-Paredes, Karina; Filice, Marco; Zamorano, Jose Luis; Saura, Marta; Zaragoza, Carlos; Botana, Laura; Francisco de Vitoria University (España); Unión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF); Comunidad de Madrid (España); Complutense University of Madrid (España)(1) Background: Early response after acute myocardial infarction (AMI) prevents extensive cardiac necrosis, in which inflammation resolution, including expression of anti-inflammatory interleukin-10 (IL-10), may play a key role. (2) Methods: We synthesized NIL10, a micelle-based nanoparticle, to target IL-10 receptor in mice and pigs subjected to AMI. (3) Results: Administration of NIL10 induced cardiac protection of wild-type and IL-10 knockout mice and pigs subjected to AMI. Cardiac protection was not induced in IL-10-receptor null mice, as shown by a significant recovery of cardiac function, in which inflammatory foci and fibrosis were strongly reduced, together with the finding that resolving M2-like macrophage populations were increased after day 3 of reperfusion. In addition, anti-inflammatory cytokines, including IL-4, IL-7, IL-10, IL-13, IL-16, and IL-27 were also elevated. Mechanistically, NIL10 induced activation of the IL-10 receptor/STAT-3 signaling pathway, and STAT3-dependent inhibition of nuclear translocation of pro-inflammatory NF-ĸB transcription factor. (4) Conclusions: Taken together, we propose using NIL10 as a novel therapeutic tool against AMI-induced cardiac damage.Publication Tumor necrosis factor-like weak inducer of apoptosis or Fn14 deficiency reduce elastase perfusion-induced aortic abdominal aneurysm in mice(American Heart Association (AHA), 2014-08-04) Tarín, Carlos; Fernández-Laso, Valvanera; Sastre, Cristina; Madrigal-Matute, Julio; Gómez, Mónica; Zaragoza, Carlos; Egido, Jesús; Burkly, Linda C; Martín-Ventura, Jose L; Blanco-Colio, Luis M; Instituto de Salud Carlos III; Fundación Conchita Rábago de Jiménez Díaz; Sociedad Española de ArteriosclerosisBACKGROUND: Abdominal aortic aneurysm (AAA) involves leukocyte recruitment, inflammatory cytokine production, vascular cell apoptosis, neovascularization, and vascular remodeling, all of which contribute to aortic dilatation. Tumor necrosis factor-like weak inducer of apoptosis (TWEAK) is a cytokine implicated in proinflammatory responses, angiogenesis, and matrix degradation but its role in AAA formation is currently unknown. METHODS AND RESULTS: Experimental AAA with aortic elastase perfusion in mice was induced in wild-type (WT), TWEAK deficient (TWEAK KO), or Fn14-deficient (Fn14 KO) mice. TWEAK or Fn14 KO deficiency reduced aortic expansion, lesion macrophages, CD3(+) T cells, neutrophils, CD31(+) microvessels, CCL2 and CCL5 chemokines expression, and MMP activity after 14 days postperfusion. TWEAK and Fn14 KO mice also showed a reduced loss of medial vascular smooth muscle cells (VSMC) that was related to a reduced number of apoptotic cells in these animals compared with WT mice. Aortas from WT animals present a higher disruption of the elastic layer and MMP activity than those from TWEAK or Fn14 KO mice, indicating a diminished vascular remodeling in KO animals. In vitro experiments unveiled that TWEAK induces CCL5 secretion and MMP-9 activation in both VSMC and bone marrow-derived macrophages, and decrease VSMC viability, effects dependent on Fn14. CONCLUSIONS: TWEAK/Fn14 axis participates in AAA formation by promoting lesion inflammatory cell accumulation, angiogenesis, matrix-degrading protease expression, and vascular remodeling. Blocking TWEAK/Fn14 interaction could be a new target for the treatment of AAA.