Abstract
Pathological remodeling during cardiac disease is a detrimental response characterized by cardiomyocyte hypertrophy and fibroblast activation, which can ultimately lead to heart failure. Genome wide expression analysis on full heart tissue have been instrumental for the identification of molecular mechanisms at play. However, these data so far were based on signals derived from all cardiac cell types and a more specific view on molecular changes driving cardiomyocyte hypertrophy and failure could aid in the development of therapies aimed at improving maladaptive remodeling. Here, we generated a cardiomyocyte-specific reporter mouse (Myh6-Cre-tdTomato) that we exposed to pressure overload by transverse aortic banding (TAB). Using Fluorescence-activated Cell Sorting (FACS) we collected both hypertrophic (one week after TAB) and failing (eight weeks after TAB) cardiomyocytes. Using these cells, we performed RNA-seq and obtained subsets of genes and pathways differentially regulated and specific for either the hypertrophic or failing stages. Among these upregulated genes we identified known marker genes for cardiomyocyte failure, such as Nppb and Myh7, but also identified genes that so far have not been linked to a failing state. RNA-seq on failing and healthy human heart samples confirmed the increased expression for several of these genes regulated during cardiomyocyte failure and allowed us to show an expressional correlation to NPPB/MYH7. Moreover, we could recapitulate the upregulation of these novel genes in stressed human induced-pluripotent stem cell (iPSC)-derived cardiomyocytes. We discovered that phosphofructokinase-platelet (PFKP) protein, a glycolytic enzyme, is strongly induced in human failing cardiomyocytes. Currently, ongoing studies are focused on defining the functional relevance of the novel failure related genes in stressed iPS-derived cardiomyocytes. Our findings suggest that cardiomyocyte-specific transcriptomic analysis allows for the identification of hypertrophic and failing gene expression profiles and helps to unveil novel genes relevant for heart disease.
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