Unexpected! “Science” revealed by Dr. Cao Yang and others: Molecules from the liver regulate important functions of the heart

▎WuXi AppTec Content Team Editor

The 2022 Nobel Prize in Physiology or Medicine will be announced soon,

In our body, the interactions between different organs are critical to maintaining homeostasis. This interaction, mediated by small molecules such as secreted proteins, also holds a key mechanism for overcoming deadly diseases.

Recently, the team of Aldons Jake Lusis of the University of California, Los Angeles published an article in the journal “Science”, which revealed that the coagulation factor XI secreted by the liver is regulated by the interaction between the heart and the liver. New roles for the heart and new potential targets for the treatment of heart failure.

Ejection fraction is an important measure of cardiac function, which refers to the percentage of ventricular end-diastolic volume that the output per beat accounts for. Heart failure is divided into two categories based on changes in ejection fraction: heart failure with reduced ejection fraction (HFrEF), and heart failure with preserved ejection fraction (HFpEF). As the name implies, the heart muscle becomes stiff and diastolic function is impaired in the latter, but the ejection fraction does not change, a symptom that accounts for about half of heart failure patients.

The first author of the paper, Dr. Cao Yang, an assistant researcher in Professor Lusis’s laboratory, said that the situation of HFpEF is much more complicated than the more in-depth study of HFrEF. Its inflammatory and metabolic disturbances involve multiple organs outside the heart, including the liver, lungs, and kidneys. Due to the complex causes and treatments, many drugs that are effective for HFrEF have no obvious effect on HFpEF. Except for the recently proposed SGLT2 inhibitors (hypoglycemic drugs), there is currently no effective drug for the treatment of HFpEF. Therefore, the scientific community urgently needs to understand the mechanism of HFpEF and find effective treatments.

In the latest study, Professor Lusis’s team analyzed the interaction between the heart and the liver. The functions of the heart and liver are closely linked and affect each other. For example, patients with nonalcoholic fatty liver disease have a higher risk of heart failure; patients with heart failure also have acute or chronic liver disease. Therefore, the research team hypothesized that the secreted protein regulates the interaction of the two organs and may be related to heart failure.

To uncover the link, the research team first needed to systematically screen for factors that mediate the liver-heart interaction. To this end, the authors utilized about 100 inbred mouse strains of different genetic backgrounds, the Hybrid Mouse Diversity Panel (HMDP). By performing high-throughput RNA sequencing of liver and heart tissues from about 100 mouse strains in HMDP and establishing the HMDP database, the authors screened and predicted secreted proteins that were highly correlated with the cardiac transcriptome.

Through further verification, the study found that Coagulation factor XI (FXI) can also mediate cardiac function in addition to the role of blood coagulation.

Image source: 123RF

In the mouse model of HFpEF, higher blood levels of FXI were associated with better diastolic function and less damage. Next, the research team verified this conclusion with mouse models with FXI overexpression and knockout in the liver, respectively. The diastolic function of FXI-overexpressing mice was improved, while the diastolic function of FXI-knockout mice was worse.

FXI is a factor in the intrinsic coagulation pathway, and its activation promotes the activation of coagulation factor IX, which in turn promotes coagulation. Overexpression of FXI in the HFpEF mouse model showed no significant changes in coagulation function, indicating that overexpression of FXI has other functions besides coagulation.

Subsequently, the research team furtheruncovered the specific pathway by which FXI overexpression contributes to cardiac diastolic function. In the absence of FXI, bone morphogenetic protein 7 (BMP7) binds to the extracellular matrix to form an inactive precursor molecule. And FXI can just act on the cleavage site of BMP7, promoting its separation from the extracellular matrix. Therefore, when FXI is overexpressed, BMP7 turns to bind to SMAD1/5 receptors on the cell membrane, promoting the phosphorylation of SMAD1/5.

Next, phosphorylated SMAD1/5 can bind to SMAD4 in the nucleus and repress the expression of genes related to inflammation and fibrosis, thereby attenuating inflammation and fibrosis in the heart and improve cardiac diastolic function.

▲Schematic diagram of the mechanism by which FXI overexpression contributes to diastolic function (Image source: Reference [1])

Thus, the study revealed that FXI overexpression promotes the activation of the BMP7-SMAD1/5 pathway in the heart, thereby improving the diastolic function of the heart and relieving the whole process of HFpEF.

Subsequent studies further validated this mechanism. After mutating the proteolytic region of FXI, its regulation of SMAD1/5 phosphorylation disappeared, indicating that the regulation of BMP7-SMAD1/5 by FXI is dependent on its proteolytic activity. In HFpEF patients, the level of FXI in the blood was significantly negatively correlated with cardiac diastolic dysfunction, suggesting that FXI has a similar effect in HFpEF patients.

As to the significance of this progress, Dr. Yang Cao pointed out that this study revealed that FXI has the effect of protecting diastolic function damage in HFpEF, which is independent based on traditionally discovered coagulation pathways. In view of the early discovery of the risk of blood coagulation and thrombus involved in the regulation of FXI on cardiovascular disease, the application of FXI in the treatment of HFpEF should require more research. But its downstream BMP7-SMAD1/5 pathway may be a key target for researching therapeutic methods. Next, the research team will continue to study the effects of other tissues, such as adipose tissue, on the heart and HFpEF.

References:

[1] Y. Cao et al, Liver-heart cross-talk mediated by coagulation factor XI protects against heart failure, Science(2022). DOI: science.org/doi/10.1126/ science.abn0910