Papel de las cardiocinas FGF21 y Metrnl en la hipertrofia cardíaca

Abstract

El objetivo principal de esta tesis fue el estudio de la función de dos nuevas cardiocinas, FGF21 y Metrnl, durante el desarrollo de la patología cardíaca. Se dividió en los siguientes apartados:

PARTE 1:

Caracterización del papel de la proteína FGF21 en corazón en un contexto de obesidad, utilizando como modelo ratones deficientes en esta proteína sometidos a una dieta rica en grasas. Estudio de los mecanismos mediante los cuales FGF21 lleva a cabo su función cardioprotectora en estas condiciones.

PARTE 2:

Caracterización de la proteína Metrnl como nueva cardiocina y potencial biomarcador de patología cardíaca. Estudio de las funciones de esta proteína en corazón en un contexto de hipertrofia cardíaca, utilizando como modelo ratones deficientes en Metrnl y la recuperación de la expresión cardíaca de Metrnl mediante vectores adeno-asociados y estudios in vitro utilizando el modelo de cardiomiocitos neonatales en cultivo.

Cardiokines are proteins produced and secreted by the heart, that have an important role in the correct maintenance of its function. In the present work, a new role for FGF21 (Fibroblast Growth Factor 21) has been described. Also, we prove that Metrnl (Meteorin-like) is a novel cardiokine with relevant cardioprotective functions. Our group first reported that FGF21 is responsible for cardioprotective mechanisms against hypertrophy development and oxidative stress. FGF21 is a secretable protein with a well-known role in glucose homeostasis regulation, ketogenesis and thermogenic activation, though the potential FGF21 protection against obesity effects in the heart remained unknown to the date. Therefore, in the present work we first describe how FGF21 deficiency causes excessive myocardial accumulation of lipidic vessels, leading to hypertrophy and cardiac dysfunction. FGF21 protective actions against lipotoxicity are mediated by autophagy (and lipophagy) increased activity, due directly to FGF21 signaling pathway activation. Metrnl is a protein secreted by the adipose tissue and the skeletal muscle, that increases energy expenditure and decreases inflammation. Although Metrnl is highly expressed in the cardiac muscle, as far as we know there are no reports regarding its cardiac function. Here we first characterized Metrnl as a new cardiokine, produced and secreted mostly by cardiomyocytes. Metrnl expression is increased in response to a wide range of cardiac stress conditions, and it has autocrine effects in the cardiomyocytes as well, where Metrnl increases PGC1α expression, a transcriptional co-activator with extensively reported anti-hypertrophic properties. Metrnl absence induces cardiac alterations, that include an anomalous hypertrophy pattern where the interventricular septum thickness is increased, more fibrosis and changes in the activation profile of cardiac immune cells. Metrnl expression recovery is enough to correct those alterations and to protect against cardiac hypertrophy. Finally, Metrnl potential as a cardiac pathology biomarker has been evaluated within a large cohort of patients with heart failure. We concluded that Metrnl is a strong prognostic biomarker of survival in these patients. As a summary, the present work contributes to a better understanding of the roles of the cardiokines FGF21 and Metrnl, and its relevance for the maintenance of the cardiac function.