Endothelial regulators of heart failure

• Applicants: Dr. Thomas Helbing; Professor Dr. Martin Moser
• Subject Area: Cardiology, Angiology
• Term: from 2016 to 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 299106849

Heart failure is a global pandemic affecting an estimated 26 million people worldwide. Diastolic dysfunction is a key feature of chronic heart failure patients. The morphological correlate of diastolic dysfunction is cardiac fibrosis characterized by cardiac remodeling with loss of microvasculature and excessive deposition of extracellular matrix. The high incidence of chronic heart failure on the one hand and the poor prognosis on the other hand underline the need for novel targets to develop therapies for heart failure patients.The cardiac endothelium plays an essential role in the development of heart failure. A better understanding of cardiac endothelium holds the potential to identify innovative heart failure therapies. To date gene expression profiles of failing hearts are dominated by gene regulation of cardiomyocytes and fibroblasts and provide minor insights in endothelium-related signaling pathways. The goal of the present project is to understand cardiac endothelium in heart failure induced by transverse aortic constriction (TAC), a well-established mouse model of left ventricular hypertrophy and fibrosis. For this purpose TAC was performed in Tie2-GFP reporter mice that express green fluorescent protein (GFP) specifically in endothelial cells. After two weeks the heart was digested and the single cell suspension was sorted by FACS to isolate Tie2-GFP positive cardiac endothelial cells. Afterwards gene expression of Tie2-GFP positive cardiac endothelial cells of hearts after TAK or sham operation was compared by cDNA microarrays. These unpublished data contain several differentially expressed transcripts that are established regulators of inflammation or mesenchymal transformation of endothelial cells. Both mechanisms are crucial for the pathogenesis of heart failure. Furthermore, one of the most upregulated transcripts after TAC was semaphorin (Sema) 3F, that is known to control neuronal axon guidance and tumor angiogenesis. The role of Sema3F in cardiac disease is unknown. The present project aims to characterize the regulation (Aim A1-3), function (Aim B1-4) and involved signaling pathways of endothelial Sema3F (Aim C1-3) in the pathogenesis of heart failure.Our preliminary observations reveal that Sema3F is increased in cultured cardiac endothelial cells in response to hypoxia or inflammatory mediators. Upregulated Sema3F augmented leukocyte recruitment to the inflamed tissue by interaction with the neuropilin receptor 2 and enhanced expression of endothelial PECAM-1. Beyond cardiac inflammation Sema3F inhibited VEGF-induced angiogenesis of cardiac endothelial cells in in vitro assays.Taken together our data suggest that characterization of endothelial Sema3F in cardiac fibrosis will lead to novel strategies in the treatment of heart failure.

• DFG Programme: Research Grants