Liver-heart cross-talk mediated by coagulation factor XI protects against heart failure.
Yang CaoYuchen WangZhenqi ZhouCalvin PanLing JiangZhiqiang ZhouYonghong MengSarada CharugundlaTao LiHooman AllayeeMarcus M SeldinAldons J LusisPublished in: Science (New York, N.Y.) (2022)
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.
Keyphrases
- heart failure
- extracellular matrix
- atrial fibrillation
- left ventricular
- mesenchymal stem cells
- oxidative stress
- genome wide
- epithelial mesenchymal transition
- signaling pathway
- type diabetes
- metabolic syndrome
- machine learning
- dna methylation
- gene expression
- bone regeneration
- transcription factor
- cardiac resynchronization therapy
- dna binding
- wild type