Cardiomyocyte - Endothelial Cell Crosstalk in Diastolic Dysfunction

Junyu Fan (Heidelberg)1, S. Nazir (Heidelberg)1, J. Huang (Heidelberg)1, J. Tyedmers (Heidelberg)1, J. Backs (Heidelberg)1

1Universitätsklinikum Heidelberg Innere Medizin VIII, Institut für Experimentelle Kardiologie Heidelberg, Deutschland


Heart failure with preserved ejection fraction (HFpEF) accounts for approximately 50% of all cases of heart failure. A hallmark of HFpEF is left ventricular stiffness caused by both increased stiffness of cardiomyocytes and fibrosis, leading to diastolic dysfunction. Endothelial cells are able to contribute to fibrosis by endothelial-mesenchymal transition (EndMT), stimulating an inflammatory response, participating in vascular rarefaction and angiogenesis, or secreting profibrotic factors in various conditions. Preliminary data from the Backs lab have revealed that a cardiomyocyte-specific knock-out of HDAC4 protects mice from HFpEF and perivascular fibrosis. To investigate how HDAC4 contributes to the development of diastolic dysfunction, we aim to investigate HDAC4-dependent cell-cell communication between cardiomyocytes and endothelial cells in HFpEF. In an in vivo approach, BL6N mice were subjected to high-fat diet and L-NAME treatment and developed diastolic dysfunction, while daily application of a Class IIa HDAC inhibitor rescued the diastolic function. To study how HDAC4 might influence fibrosis, a quantitative mass spectrometry analysis of left ventricular extracellular matrix (ECM) was performed and discovered an altered ECM profile induced by high-fat diet and L-NAME. Thus, we hypothesize that HDAC4 is crucial for secretion of cardiocrine factors that induce changes in ECM composition. To identify these potential factors, we employed an in vitro approach using neonatal rat ventricular cardiomyocytes (NRVMs). To mimic HFpEF conditions, we treated the cells with palmitic acid and L-NAME. Culture supernatant from the treated cardiomyocytes were added to human coronary artery endothelial cells to study the effect of cardiocrine factors secreted from cardiomyocytes on endothelial cells. We observed that the cell culture supernatant induced α-SMA expression in endothelial cells, suggesting that the endothelial cells undergo EndMT. Subsequently, cardiomyocyte secretome analysis from NRVMs, will be used to discover molecular players in the mechanism of HDAC4-dependent induction of EndMT that contributes to the development of diastolic dysfunction. The results of this study may help revealing the underlying molecular mechanisms of HFpEF and could offer potential new therapeutic targets.

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