Abstract
Pathological cardiac hypertrophy is a leading cause of heart failure, but knowledge of the full repertoire of cardiac cells and their gene expression profiles in the human hypertrophic heart is missing. Here, by using large-scale single-nucleus transcriptomics, we present the transcriptional response of human cardiomyocytes to pressure overload caused by aortic valve stenosis and describe major alterations in cardiac cellular crosstalk. Hypertrophied cardiomyocytes had reduced input from endothelial cells and fibroblasts. Genes encoding Eph receptor tyrosine kinases, particularly EPHB1, were significantly downregulated in cardiomyocytes of the hypertrophied heart. Consequently, EPHB1 activation by its ligand ephrin (EFN)B2, which is mainly expressed by endothelial cells, was reduced. EFNB2 inhibited cardiomyocyte hypertrophy in vitro, while silencing its expression in endothelial cells induced hypertrophy in co-cultured cardiomyocytes. Our human cell atlas of the hypertrophied heart highlights the importance of intercellular crosstalk in disease pathogenesis and provides a valuable resource.
Highlights
Pathological cardiac hypertrophy is a leading cause of heart failure, but knowledge of the full repertoire of cardiac cells and their gene expression profiles in the human hypertrophic heart is missing
The present study reveals a profound dysregulation of genes in cardiomyocytes of hypertrophied hearts of patients suffering from aortic valve stenosis (AS), of which many are involved in regulating the interaction of cardiomyocytes with other non-parenchymal cells
We identified extensive dysregulation of the Eph receptor EPHB1 in human cardiac hypertrophy, highlighting the importance of this pathway for future therapeutic interventions
Summary
Pathological cardiac hypertrophy is a leading cause of heart failure, but knowledge of the full repertoire of cardiac cells and their gene expression profiles in the human hypertrophic heart is missing. By using large-scale single-nucleus transcriptomics, we present the transcriptional response of human cardiomyocytes to pressure overload caused by aortic valve stenosis and describe major alterations in cardiac cellular crosstalk. Cardiac ischemia or pressure overload induces the expression of vascular endothelial growth factor (VEGF)A in cardiomyocytes to induce endothelial cell proliferation and angiogenic responses[4]. We provide an analysis of the human hypertrophied heart of patients suffering from aortic valve stenosis (AS), which discloses insights into the transcriptional adaptation of cardiomyocytes and the impact on interactions with other cell types in the diseased hypertrophied heart
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