Liver-heart cross-talk mediated by coagulation factor XI protects against heart failure

Tissue-tissue communication by endocrine factors is a vital mechanism for physiologic homeostasis. A systems genetics analysis of transcriptomic and functional data from a cohort of diverse, inbred strains of mice predicted that coagulation factor XI (FXI), a liver-derived protein, protects against diastolic dysfunction, a key trait of heart failure with preserved ejection fraction. This was confirmed using gain- and loss-of-function studies, and FXI was found to activate the bone morphogenetic protein (BMP)-SMAD1/5 pathway in the heart. The proteolytic activity of FXI is required for the cleavage and activation of extracellular matrix-associated BMP7 in the heart, thus inhibiting genes involved in inflammation and fibrosis. Our results reveal a protective role of FXI in heart injury that is distinct from its role in coagulation.

Automated summary

Tissue-tissue communication through endocrine factors is crucial for physiological homeostasis. A study on mice showed that coagulation factor XI (FXI), a protein derived from the liver, protects against diastolic dysfunction, a key trait of heart failure with preserved ejection fraction. FXI was found to activate the BMP-SMAD1/5 pathway in the heart and inhibit genes associated with inflammation and fibrosis, by cleaving and activating extracellular matrix-associated BMP7. This study reveals a protective role of FXI in heart injury that is separate from its role in blood coagulation.