Myocardial infarction; Cardiac regeneration; microRNAs; long non-coding RNAs; Mouse; Zebrafish
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Ounzain Samir, Genome-wide profiling of the cardiac transcriptome after myocardial infarction identifies novel heart-specific long noncoding RNAs, in European Heart Journal
Cardiovascular diseases, and in particular heart failure, are leading causes of death. Heart failure is a progressive disorder initiated by a loss of cardiomyocytes. The primary event can be either acute, for instance after myocardial infarction, or gradual, for instance in patients suffering from chronic hypertension. The mammalian heart adapts to new hemodynamic conditions via induction of hypertrophy in viable cardiomyocytes. However, evidence suggests that myocytes could also be replaced continuously in the heart through a process involving replication, differentiation, aging, senescence and death. This indicates that, akin of prototypic self-renewing tissues, the heart could possess the basic and necessary elements for tissue regeneration. Regeneration may rely on populations of resident cardiac stem cells that could be activated upon cardiac damage to produce committed cardiac precursor cells. Despite the mobilization of cardiac stem cells, the adult mammalian heart has limited regenerative capacity. Instead, lost myocytes are mostly replaced by fibrotic scar tissue. In sharp contrast to mammals, organisms such as the zebrafish can regenerate their amputated heart. Regeneration of the zebrafish heart requires a complex action of mechanisms including progenitor recruitment, myocyte dedifferentiation, undifferentiated cell proliferation, pattern generation and cardiogenic differentiation. Regeneration replaces lost cardiac tissues in about a month, and, consequently, little or no fibrosis is observed. Recently, miRNAs have emerged as new regulators of gene expression. These non-coding RNA molecules regulate gene expression by either inducing messenger RNA degradation or by inhibiting translation. In the heart, modulation of miRNAs controls the development of cardiac hypertrophy and fibrosis in both the non-regenerating mammalian heart and in the regenerating zebrafish heart. Therefore, miRNAs could be used to shift the response to injury in the mammalian heart towards cardiomyocyte proliferation, stem cell recruitment and cardiogenic differentiation. It is, therefore, the goal of the current project to identify such miRNAs by comparing the cardiac response to injury in two relevant animal models, the mouse and the zebrafish. This project will take advantage of the latest technology in deep sequencing, transcriptomics and bioinformatics analysis to identify the miRNAs and their target genes that are differently modulated after myocardial infarction in the mouse and after ventricular resection in the zebrafish. The biological relevance and therapeutic potential of the identified miRNAs and target genes will be evaluated in vitro and in vivo.