Interferon stimulated gene 15 pathway is a novel mediator of endothelial dysfunction and aneurysms development in angiotensin II infused mice through increased oxidative stress.
Por:
González-Amor M, García-Redondo AB, Jorge I, Zalba G, Becares M, Ruiz-Rodríguez MJ, Rodríguez C, Bermeo H, Rodrigues-Díez R, Rios FJ, Montezano AC, Martínez-González J, Vázquez J, Redondo JM, Touyz RM, Guerra S, Salaices M, Briones AM
Publicada:
1 ene 2022
Ahead of Print:
21 oct 2021
Resumen:
AIMS: Interferon-stimulated gene 15 (ISG15) encodes an ubiquitin-like protein that induces a reversible post-translational modification (ISGylation) and can also be secreted as a free form. ISG15 plays an essential role as host-defense response to microbial infection; however, its contribution to vascular damage associated to hypertension is unknown. METHODS AND RESULTS: Bioinformatics identified ISG15 as a mediator of hypertension-associated vascular damage. ISG15 expression positively correlated with systolic and diastolic blood pressure and carotid intima-media thickness in human peripheral blood mononuclear cells. Consistently, Isg15 expression was enhanced in aorta from hypertension models and in angiotensinII (AngII)-treated vascular cells and macrophages. Proteomics revealed differential expression of proteins implicated in cardiovascular function, extracellular matrix and remodeling, and vascular redox state in aorta from AngII-infused ISG15-/- mice. Moreover, ISG15-/- mice were protected against AngII-induced hypertension, vascular stiffness, elastin remodeling, endothelial dysfunction, and expression of inflammatory and oxidative stress markers. Conversely, mice with excessive ISGylation (USP18C61A) show enhanced AngII-induced hypertension, vascular fibrosis, inflammation and reactive oxygen species (ROS) generation along with elastin breaks, aortic dilation and rupture. Accordingly, human and murine abdominal aortic aneurysms showed augmented ISG15 expression. Mechanistically, ISG15 induces vascular ROS production, while antioxidant treatment prevented ISG15-induced endothelial dysfunction and vascular remodeling. CONCLUSION: ISG15 is a novel mediator of vascular damage in hypertension through oxidative stress and inflammation. TRANSLATIONAL PERSPECTIVE: Recent evidence from randomized clinical trials demonstrate the effectiveness of specific anti-inflammatory treatments in cardiovascular prevention. In this study we have identified a new inflammatory mediator involved in vascular damage in experimental and human hypertension and aneurysms. We found that interferon stimulated gene 15 (ISG15) is increased at the vascular level in animal models of hypertension and aneurysms. More importantly, ISG15 correlates with human hypertension, vascular remodeling, and aneurysms presence. Underlying mechanisms responsible for vascular damage induced by ISG15 include oxidative and inflammation. Our results further support the role of inflammation in vascular damage in different cardiovascular pathologies.
Filiaciones:
González-Amor M:
Departamento de Farmacología, Universidad Autónoma de Madrid. Instituto de Investigación Hospital La Paz., Madrid, Spain
Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares (CIBERCV), Spain
García-Redondo AB:
Departamento de Farmacología, Universidad Autónoma de Madrid. Instituto de Investigación Hospital La Paz., Madrid, Spain
Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares (CIBERCV), Spain
Jorge I:
Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares (CIBERCV), Spain
Laboratorio de Proteómica Cardiovascular, Centro Nacional de Investigaciones Cardiovasculares., Madrid, Spain
Zalba G:
Departamento de Bioquímica y Genética, Universidad de Navarra. Instituto de Investigación Sanitaria de Navarra, Pamplona, Spain
Becares M:
Departamento de Medicina Preventiva y Microbiología, Universidad Autónoma de Madrid. Instituto de Investigación Hospital La Paz Madrid, Spain
Ruiz-Rodríguez MJ:
Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares (CIBERCV), Spain
Grupo de Regulación Génica en remodelado cardiovascular e inflamación. Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain
Rodríguez C:
Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares (CIBERCV), Spain
Institut de Recerca Hospital de la Santa Creu i Sant Pau-Programa ICCC, Barcelona. Instituto de Investigación Biomédica Sant Pau, Barcelona, Spain
Bermeo H:
Departamento de Farmacología, Universidad Autónoma de Madrid. Instituto de Investigación Hospital La Paz., Madrid, Spain
Rodrigues-Díez R:
Departamento de Farmacología, Universidad Autónoma de Madrid. Instituto de Investigación Hospital La Paz., Madrid, Spain
Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares (CIBERCV), Spain
Rios FJ:
Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, UK
Montezano AC:
Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, UK
Martínez-González J:
Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares (CIBERCV), Spain
Instituto de Investigaciones Biomédicas de Barcelona-CSIC, Barcelona, Spain. Instituto de Investigación Biomédica Sant Pau, Barcelona, Spain
Vázquez J:
Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares (CIBERCV), Spain
Laboratorio de Proteómica Cardiovascular, Centro Nacional de Investigaciones Cardiovasculares., Madrid, Spain
Redondo JM:
Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares (CIBERCV), Spain
Grupo de Regulación Génica en remodelado cardiovascular e inflamación. Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain
Touyz RM:
Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, UK
Guerra S:
Departamento de Medicina Preventiva y Microbiología, Universidad Autónoma de Madrid. Instituto de Investigación Hospital La Paz Madrid, Spain
Salaices M:
Departamento de Farmacología, Universidad Autónoma de Madrid. Instituto de Investigación Hospital La Paz., Madrid, Spain
Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares (CIBERCV), Spain
Briones AM:
Departamento de Farmacología, Universidad Autónoma de Madrid. Instituto de Investigación Hospital La Paz., Madrid, Spain
Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares (CIBERCV), Spain
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