Molecular characterization of vascular pathogenesis

Research summary:

We are interested in uncovering novel mediators of cardiovascular pathogenesis, one of the major causes of death worldwide, because these mediators might become novel targets for therapeutic intervention. To this end, we use a combination of in vitro and in vivo experimental approaches involving transcriptomics, proteomics, cellular and molecular analysis, mouse models, and advanced imaging techniques.

Our pioneering studies, in collaboration with the group of Dr. J.M. Redondo (CNIC), show that deficiency of the metalloproteinase Adamts1 leads to thoracic aorta aneurysm (TAA) in mice due to increased Nos2-dependent NO production. We also showed that TAA was reversed using pharmacological NOS2 inhibition in mouse models, raising the possibility that blocking NO signaling could be a novel treatment for TAA. Indeed, we are pursuing clinical trials with NOS2 inhibitors in Marfan syndrome, a heritable life-threatening disease in which TAA accounts for over 90% of its mortality. These findings changed our view of the pathophysiology of TAA and prompted us to further explore the molecular and biomechanical mechanisms of TAA in collaboration with other international research groups. Much of our recent effort focuses on the identification of additional mediators of these diseases.

We also search for genes mediating pathological vascular wall remodeling, a key process in the development of hypertension and arterial diseases such as atherosclerosis and aneurysm. We had determined that calcineurin and its downstream effector Rcan1 are essential mediators of atherosclerosis, restenosis, and abdominal aorta aneurysm (AAA). Our studies allowed the identification of new pathophysiological mechanisms and new therapeutic targets in aortic diseases. Using tissue-specific inducible knockout mice, we have also uncovered a homeostatic role for Rcan1 in the aorta and that its genetic inactivation in the adult mouse predisposes to hypertension-induced intramural hematoma and subsequent AAA through mechanisms involving GSK-3b, ROCK and smooth muscle Myosin. These results prompted us to follow new exciting avenues of research into the pathogenesis of aortic diseases. In particular, we have initiated a comprehensive study aimed at identifying the role of calcineurin in the aortic transcriptome, proteome, and phosphoproteome regulated by hypertensive stimuli such as angiotensin II. We believe that these studies will identify therapeutic targets for AAA and novel therapeutic targets for arterial hypertension.

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Figure 1. Transcriptomics, proteomics, tissue staining analysis, and primary cell cultures of mouse models of disease and/or patient-derived samples are used to dissect the major signaling pathways that cause arterial diseases, such as aortic aneurysm and arterial hypertension, and identify novel targets for therapeutic intervention. Genetic manipulation and in vivo lentiviral-mediated transduction are then used to generate new mouse models for validation of these targets. The efficacy of novel treatments is assessed longitudinally in vivo by ultrasound imaging of the heart and vessels and ex vivo by tissue analysis.

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Campanero GarcíaMiguel R.2274566mcampanero(at)cbm.csic.esE. Investigadores Científicos de Organismos Públicos

Relevant publications:

  • A. de la Fuente-Alonso, M. Toral, A. Alfayate, M.J. Ruiz-Rodríguez, E. Bonzón-Kulichenko, G. Teixido-Tura, M.J. Méndez-Olivares, D. López-Maderuelo, I. González-Valdés, E. García-Izquierdo, S. Mingo, C.E. Martín, L. Muiño-Mosquera, J. De Backer, J.F. Nistal, A. Forteza, A. Evangelista, J. Vázquez, *M.R. Campanero, and *JM Redondo. *Co-senior & corresponding authors. Aortic disease in Marfan syndrome is caused by overactivation of sGC-PRKG signaling by NO. Nat. Commun. (under second revision) (2020).
  • C. Martín-Cortázar, Y. Chiodo, R. Jiménez-P., M. Bernbé, M.L. Cayuela, T. Iglesias, and M.R. Campanero. CDCA7 finely tunes cytoskeleton dynamics to promote lymphoma migration and invasion. Haematologica. 105(3): 730-740 (2020). IF2019: 7,12 (7/76 in Hematology).
  • S Villahoz, PS Yunes-Leites, N Méndez-Barbero, K Urso, E.Bonzon-Kulichenko, S Ortega, J Vazquez, S Offermanns, *JM Redondo, and *MR Campanero. *Co-senior & corresponding authors. Conditional deletion of Rcan1 predisposes to hypertension-mediated aortic intramural hematoma and subsequent aneurysm and lethal dissection. Nat Commun 9(1): 4795 (2018). IF2018: 11,88 (5/69 in Multidisciplinary Sciences).
  • R. Jiménez-P., C. Martín-Cortázar, O. Kourani, Y. Chiodo, R. Cordoba, M.P. Domínguez-Franjo, J.M. Redondo, T. Iglesias, and M.R. Campanero. CDCA7 is a critical mediator of lymphomagenesis that selectively regulates anchorage-independent growth. Haematologica. 103(10): 1669-1678 (2018). IF2018: 7,57 (7/73 in Hematology).
  • J. Oller, N. Méndez-Barbero, E.J. Ruiz, S. Villahoz, M. Renard, L.I. Canelas, A.M. Briones, R. Alberca, N. Lozano-Vidal, M.A. Hurlé, D. Milewicz, A. Evangelista, M. Salaices, J.F. Nistal, L.J. Jiménez-Borreguero, J. DeBacker, *M.R. Campanero, and *J.M. Redondo. *Co-senior & corresponding authors. Nitric oxide mediates aortic disease in mice deficient in the metalloprotease Adamts1 and in a mouse model of Marfan syndrome. Nat. Med. 23(2): 200-212 (2017). IF 2017: 32,62 (1/124 in Medicine, Research & Experimental). Destacado por Science: http://science.sciencemag.org/content/355/6324/twil; Destacado por Biocentury: Inducible nitric oxide synthase 2 (NOS2; iNOS).
  • J. Alvaro-Blanco, Y. Chiodo, K. Urso, C. Martín-Cortázar, O. Kourani, M. Rodriguez-Martinez, E. Calonge, J. Alcamí, J.M. Redondo, T. Iglesias, and M.R. Campanero. MAZ induces MYB expression during the exit from quiescence via de E2F site in the MYB promoter. Nucleic Acids Res. 45(17): 9960-9975 (2017). IF2017: 11,56 (14/286 in Biochemistry & Molecular Biology).
  • J. Oller, A. Alfranca, N. Méndez-Barbero, S. Villahoz, N. Lozano-Vidal, M. Martín-Alonso, A.G. Arroyo, A. Escolano, A.L. Armesilla, *M.R. Campanero*, and *J.M. Redondo. *Co-senior & corresponding authors. C/EBPß and NFAT differentially regulate Adamts1 induction by stimuli associated with vascular remodeling. Mol. Cell Biol. 35(19): 3409-3422 (2015). IF 2015: 4,43 (66/289 in Biochemistry & Molecular Biology)
  • N. Méndez-Barbero, V. Esteban, S. Villahoz, A. Escolano, K. Urso, A. Alfranca, C. Rodríguez, S.A. Sánchez, T. Osawa, V. Andrés, J. Martínez-González, T. Minami, *J.M. Redondo, and *M.R. Campanero *Co-senior & corresponding authors. A major role for RCAN1 in atherosclerosis progression. EMBO Mol. Med. 5:1901-1917 (2013). IF 2013: 8,25 (8/122 in Medicine, Research & Experimental)
  • Molina-Privado, R. Jiménez-P., S. Montes-Moreno, Y. Chiodo, M. Rodríguez-Martínez, L. Sánchez-Verde, T. Iglesias, M.A. Piris, and M.R. Campanero. E2F4 plays a key role in Burkitt lymphoma tumorigenesis. Leukemia. 26(10): 2277-2285. (2012). IF 2012: 10,16 (2/67 in Hematology; 8/196 in Oncology)
  • V Esteban, N Méndez-Barbero, LJ Jiménez-Borreguero, M Roqué, L Novensá, AB García-Redondo, M Salaices, L Vila, ML. Arbonés, *M.R. Campanero, and *JM Redondo. *Co-senior & corresponding authors. Regulator of calcineurin 1 mediates pathological vascular wall remodeling. J. Exp. Med. 208: 2125-2139. (2011). IF 2011: 13,85 (2/110 in Medicine, Research & Experimental). Seleccionado por Faculty of 1000 (Muller W: 2012. F1000.com/13418975)

Doctoral theses:

  • Irene Molina Privado (2009). Estudio de las bases moleculares de la formación del Linfoma de Burkitt para la identificación de posibles marcadores diagnósticos y dianas terapéuticas. Universidad Autónoma de Madrid. Director: Miguel R. Campanero
  • Lorena Martínez Gac (2009). Estudio de los mecanismos implicados en la regulación transcripcional de los genes CCNG2 Y C-MYC. Universidad Autónoma de Madrid. Directores: Miguel R. Campanero y Ana Clara Carrera.
  • Raúl Jiménez Pérez (2013). Identificación y caracterización funcional de genes implicados en la transformación maligna del compartimento linfocitario. Universidad Autónoma de Madrid. Director: Miguel R. Campanero.
  • Nerea Méndez Barbero (2014). Estudio del papel de calcineurina y Rcan1 en el remodelado patológico de la pared vascular. Universidad Autónoma de Madrid. Directores: Miguel R. Campanero y Juan Miguel Redondo.
  • Yuri Chiodo (2017). Cell death, cell growth and cell cycle regulation by the Retinoblastoma family. Universidad Autónoma de Madrid. Directores: Miguel R. Campanero y Juan Miguel Redondo.
  • Jorge Oller Pedrosa (2017). Identification of the metalloproteinase Adamts1 and Nitric Oxide as new therapeutic targets in aortic diseases. Universidad Autónoma de Madrid. Directores: Miguel R. Campanero y Juan Miguel Redondo.
  • Silvia Villahoz Lázaro (2018). Effects of conditional deficiency of Rcan1 in pathological vascular wall remodeling (Tesis Europea). Universidad Autónoma de Madrid. Directores: Miguel R. Campanero y Juan Miguel Redondo.
  • Carla Martín Cortázar (2019). Invasión, migración y dinámica del citoesqueleto de células de linfoma mediadas por CDCA7. Universidad Autónoma de Madrid. Director: Miguel R. Campanero.
  • Omar Kourani Méndez (2019). Papel del sistema del glutatión en la adaptación y resistencia de los tumores linfoides al estrés oxidativo. Universidad Autónoma de Madrid. Director: Miguel R. Campanero.

Licensed patents:

  • Procedimiento de identificación de pacientes con linfoma de Burkitt esporádico, procedimiento de identificación y uso de compuestos para el tratamiento de linfoma de Burkitt esporádico. I. Molina-Privado y Miguel R. Campanero. PCT/ES2008/070182. País de prioridad: Internacional salvo USA. Fecha: octubre de 2007.  Entidad titular: CSIC/UAM; Licenciada a BIOTOOLS Biotechnological & Medical Laboratories S.A. el 29 de abril de 2008.
  • In vitro method for identifying thoracic aortic aneurysms (TAA) in a subject. J.M. Redondo, J. Oller, N. Méndez-Barbero y Miguel R. Campanero. PCT/EP2016/082925. País de prioridad: Internacional excepto USA. Fecha de prioridad: marzo de 2016; Entidad titular: CNIC/CSIC/UAM. Licenciada a SPHERIUM BIOMED S.L. el 21 de septiembre de 2018. Patente USA (Nº 16/083,165) concedida el 16 de septiembre de 2020.

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