Coagulation factor with potential for the treatment of heart failure

Abstract

We recently found that coagulation factor XI (FXI), a protein exclusively produced by the liver, plays an unexpected role in the heart. 1 In the mouse model of heart failure with preserved ejection fraction (HFpEF), mice overexpressing FXI in the liver showed improved diastolic function and reduced inflammation and fibrosis. FXI overexpression activated the bone morphogenetic protein (BMP)-SMAD1/5 pathway in the heart. The action of FXI on the heart requires proteolytic activity, as point mutations in its catalytic domain eliminated effects on BMP signalling and heart function. BMP7 is secreted as an inactive precursor that binds to the extracellular matrix, and our results indicated that it was cleaved by FXI, releasing the active growth factor from the pro-domain. Results from human cohorts indicated that FXI has a similar function in humans. Our study identifies FXI as an endocrine factor that influences heart function, distinct from its role in coagulation. This previously unrecognized liver-heart interaction enriches our understanding of liver-heart communication and suggests a promising therapeutic strategy for heart failure.Inter-tissue communication via secreted proteins is a vital mechanism for proper physiologic homeostasis. We utilized a bioinformatics framework that uses natural variation in transcript levels across tissues in a panel of approximately 100 inbred strains of mice, termed the hybrid mouse diversity panel (HMDP), to identify and functionally annotate novel circuits of tissue-tissue com-This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.