Regulation and diagnosis of cardiovascular diseases by microRNAs derived from immune cells
Title (trans.)Regulación y diagnóstico de enfermedades cardiovasculares por microRNAs derivados de células inmunes
AdvisorMartín Fernández, María Pilar
EntityUAM. Departamento de Biología Molecular; Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC)
SubjectsCorazón (enfermedades); Linfocitos T; Miocardio; Biología y Biomedicina / Biología
NoteTesis doctoral inédita leída en la Universidad Autónoma de Madrid, Facultad de Ciencias, Departamento de Biología Molecular. Fecha de lectura: 14-01-2022
Esta tesis tiene embargado el acceso al texto completo hasta el 14-07-2023
Esta obra está bajo una licencia de Creative Commons Reconocimiento-NoComercial-SinObraDerivada 4.0 Internacional.
Cardiovascular diseases are the main cause of mortality and morbidity worldwide. Adequate management of acute cardiac conditions, such as myocarditis and myocardial infarction (MI), relies on an early diagnosis. However, diagnosis is often presented as a clinical challenge due to the uncharacteristic nature of their symptoms and the lack of non-invasive and cost-effective tools for discrimination. Emerging evidence acknowledges the participation of T cells in the origin and resolution of different cardiovascular disorders, constituting a broad field for the exploration of new clinical candidates. We aimed to deepen our knowledge in the T cell responses underlying myocarditis and MI, to elucidate novel molecular targets that ultimately will improve diagnosis and management of patients. In this study, we characterized that Th17 cells increase in the peripheral blood of myocarditis patients and experimental autoimmune myocarditis (EAM) mice, but not in MI patients or MI mice. Profiling of miRNAs in T cells and plasma identified mmu-miR-721 as secreted by Th17 cells into plasma extracellular vesicles (EVs) during EAM. We defined that this miRNA promotes Th17 cell responses by targeting Pparg, which is an inhibitor of RORt expression. Thus, blockade of mmu-miR-721 in vivo dampens Th17 cell responses and ameliorates EAM progression. Subsequently, hsa-miRNAChr8: 96 was cloned and validated as a human consensus sequence to the murine mmu-miR-721, which exhibits miRNA properties and is upregulated in the plasma EVs of myocarditis patients. The analysis of four independent patient cohorts validated hsa-miR-Chr8:96 as a biomarker that discriminates myocarditis from MI, other Th17-related diseases and healthy individuals. The identification of this biomarker in plasma provides an avenue for the advancement of non-invasive and accurate diagnosis of myocarditis. In a parallel study, an extensive analysis of immunological markers in MI patients showed an expansion of peripheral CD69+ Treg cells after MI. We showed that Cd69-/- mice develop strong IL-17+ T cell responses after MI that increase myocardial inflammation and, consequently, worsen cardiac function and decrease survival. Mechanistically, CD69+ Treg cells inhibit IL-17+ T cells in a CD39-dependent manner. Adoptive transfer of CD69+ Treg cells to Cd69-/- mice after MI reduces IL-17+ T cell recruitment and improves survival. Consistently, clinical data from two cohorts of patients indicate that increased CD69 expression on Treg cells after acute MI is associated with a lower risk of rehospitalization for chronic heart failure (CHF) after 2.5 years of follow-up. In addition, hsa-miR-155- 5p and CD69 expression coincide in Treg cells of MI patients. This miRNA is upregulated in the plasma of MI patients with high CD69 expression, designating those as at a low risk of developing CHF. Our data highlight that the CD69/miR-155-5p axis on Treg cells is a therapeutic and prognostic candidate for preventing MI-derived CH
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Google Scholar:Blanco Domínguez, Rafael
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