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 inmunesAuthor
Blanco Domínguez, RafaelAdvisor
Martín Fernández, María PilarEntity
UAM. Departamento de Biología Molecular; Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC)Date
2022-01-14Subjects
Corazón (enfermedades); Linfocitos T; Miocardio; Biología y Biomedicina / BiologíaNote
Tesis doctoral inédita leída en la Universidad Autónoma de Madrid, Facultad de Ciencias, Departamento de Biología Molecular. Fecha de lectura: 14-01-2022Esta 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.
Abstract
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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