Remodelado cardiaco adverso tras infarto agudo de miocardionuevos mecanismos y terapias

Abstract

Introduction Acute myocardial infarction (AMI) is a major health problem. Although its mortality in the acute phase has been reduced in recent years, its prognosis in the medium and long-term remains poor due to the structural and functional impact of myocardial necrosis. After AMI, a series of local repair mechanisms are implemented in the infarcted tissue, mainly inflammation and fibrosis, which condition a risk of ventricular arrhythmia and deterioration of systolic and diastolic myocardial function, as well as others in the non-infarcted tissue, mainly fibrosis and hypertrophy, with an initial compensatory function but which in evolution lead to pathological structural changes and loss of cardiac function. For this reason, AMI carries a high risk of death and evolution to heart failure. Several studies show how a high serum concentration of Galectin-3 or the soluble isoform sST2 identifies a poor prognosis, but also a more adverse ventricular remodeling in this type of patients. However, the molecular mechanisms that modulate their expression and signaling at the cellular level are not well known. In fact, there are no treatments aimed at specifically modulating the expression of these biomarkers. Their characterization will allow development and use of new treatments that avoid adverse myocardial remodeling after AMI improving the quality of life of our patients. The achievement of the work plan begins by studying the effect of treatment with metformin, an antidiabetic that despite having been able to improve post-AMI ventricular remodeling and delay progression to heart failure, the molecular mechanisms have not yet been described. Aims The achievement of the work plan to be developed has general objectives: (1) To characterize the molecular mechanisms associated with the expression and secretion of Gal-3 by cardiomyocytes and the study of their paracrine action on adjacent cardiac fibroblasts; and (2) To identify the elements regulating the specific expression of the isoform sST2 by the infarcted myocardium. Methodology This study was performed using an animal model of MI by ligation of the left descending anterior coronary artery. In addition, cardiomyocyte and cardiac fibroblast cultures have been used and subjected to biomechanical cell deformation protocols and Knockdown models. Ventricular remodeling after IM is studied by quantitative PCR, western blot and immunofluorescence. Cardiac function by echocardiography. Results and conclusions Phosphorylation of the AMPK enzyme induced by treatment with metformin activates tuberin which leads to blockage of the mTORC1/p70S6K intracellular signaling pathway. As a result of this process, the enzymes mitoNox and PKC are inhibited and finally there is a decrease in the expression and secretion of Gal-3 by the cardiomyocyte. In the presence of damage, Gal-3 secreted by cardiomyocytes in the acute phase of MI, induces activation of cardiac fibroblasts and thus the adverse fibrotic program. On the other hand, we have been pioneers in demonstrating the key role of the transcription factor Ying yang-1 (Yy1) on cardiac sST2 expression. Indeed, Yy1 induces increased expression of the soluble isoform sST2 under stress conditions. Inhibition of HDAC4 phosphorylation, which acts as co-repressor of Yy1, represses the expression of sST2 in the infarcted myocardium. The inhibition of the expression and secretion of sST2 facilitates the interaction between IL-33 and the transmembrane ST2L receptor, which translates into cardioprotective effects. Manipulation of Yy1 factor gene expression or its HDAC4 co-repressor may represent potential pharmacological targets to prevent adverse cardiac remodeling. Silencing the endogenous expression of Yy1 prevents increased expression of sST2 isoform but does not affect ST2L expression. Although metformin therapy decreases the expression of sST2, it also affects the expression of the transmembrane isoform ST2L, so it is not a treatment of choice that allows cardioprotective IL-33/ST2L signaling.