The unknown functions of a known protein: the case of coagulation factor XI

Authors: van der Vorst, Emiel P C; Badimon, L

Affiliations: Interdisciplinary Centre for Clinical Research (IZKF), RWTH Aachen University, 52074 Aachen, Germany. Aachen-Maastricht Institute for CardioRenal Disease (AMICARE), RWTH Aachen University, 52074 Aachen, Germany. Institute for Cardiovascular Prevention (IPEK), Ludwig-Maximilians-University Munich, 80336 Munich, Germany. Cardiovascular-Program, Institut d’Investigació Biomèdica Sant Pau (IIB Sant Pau), 08041 Barcelona, Spain. Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares (CiberCV), 28029 Barcelona, Spain.

Publication: Cardiovascular research; 2023

Abstract: Over the last years, it became clear that there is considerable cross-talk between various organs, and that this cross-talk plays an instrumental role in disease pathologies. It has for example already been well established that heart failure can unfavorably affect liver function, but also vice versa as non-alcoholic fatty liver disease can increase the risk for heart failure. This bi-directional influence between organs should be mediated by secreted proteins that can travel through the circulation. However, many of such proteins remain to be identified, which based on the importance of organ cross-talk is one of the major scientific challenges at the moment. A recent study by Cao et al. in Science identified factor XI (FXI), a coagulation factor that is exclusively produced by the liver, as a crucial factor that plays a key role in liver–heart cross-talk. In their study, a panel of 100 diverse inbred mouse strains called the Hybrid Mouse Diversity Panel (HMDP)5 was deployed to generate transcriptomic data from the heart and liver. Subsequently, correlations and predictions were made between secreted proteins from the liver and their downstream effects on the heart, resulting in a list of top-ranked candidates. Besides the gene for FXI, also genes for hepatocyte growth factor activator (HGFAC) and complement C8 gamma chain (C8G) were among the top candidates. All three genes were individually overexpressed in the livers of C57BL/6J mice using an adeno-associated virus serotype 8, directed by the liver-specific thyroid hormone-binding globulin promoter. Subsequently, mice were subjected to a model for heart failure with preserved ejection fraction (HFpEF). Although HGFAC and C8G overexpression did influent heart weight, the most remarkable effects were observed for FXI.