Endothelial-fibroblast interactions during Scarb1 accelerate heart failure

Summary Endothelial cells (ECs) maintain cardiac homeostasis and EC dysfunction causes heart failure progression. Moreover, pathological changes occur via interactions between multiple cells, including ECs. Here, we conducted single-cell RNA-seq analysis of non-cardiomyocytes in mouse hearts during heart failure progression to elucidate the pathological changes in ECs and fibroblasts (FBs) mediated by cell-cell interactions. We show that capillary and arterial ECs exhibit mesenchymal gene expression changes with heart failure progression, indicating that endothelial-to-mesenchymal transition (EndMT) is a major pathological alteration in ECs. We also found that the interaction between ECs and FBs was enriched during heart failure, particularly when involving Scavenger Receptor Class B Member 1 (Scarb1) in ECs. FBs induce mesenchymal gene alterations in ECs in the EC-FB co-culture system, which is inhibited by blocking SCARB1. RNA-seq analysis showed that administration of a SCARB1 inhibitor blocked mesenchymal gene expression, and inflammatory changes, suggesting that the EC-FB interaction via Scarb1 is important for EndMT induction in ECs. Systemic administration of a SCARB1 inhibitor attenuated heart failure progression and cardiac fibrosis. EC-specific Scarb1 knockout mouse showed improved cardiac function, suggesting a crucial role of Scarb1 in heart failure progression. Our results suggest that Scarb1 is a promising candidate for novel heart failure treatments that target ECs.