Artistic rendering of a heart

By stimulating the excessive buildup of connective tissue, signaling molecule contributes to heart disease

One of the causes of heart failure is the formation of excess connective tissue. An international team of researchers has discovered a specific treatment approach involving the signaling molecule interleukin 11. Their findings have now been published in the journal “Nature”.

Acute ischemia (lack of blood flow) and sustained high blood pressure have grave consequences for heart health: This combination results in an overproduction of collagen fibers and myocardial stiffness. The heart loses its capacity to pump blood, and its normal electrical conduction system is disrupted. Heart failure is one of the leading causes of death and disease worldwide. Preventing excessive collagen accumulation is therefore an important treatment approach.

Clearly visible in the MRT scan: a heart with hypertrophic cardiomyopathy and a fibrosis (light region)

Scientists have known for a long time that the transforming growth factor-beta (TGF-beta) triggers connective tissue production. It is not suitable, however, as a target for a specific heart medication because it also affects other signaling pathways and because a therapeutic blockade has numerous side effects.

An international team of researchers, in collaboration with the Max Delbrück Center for Molecular medicine (MDC), have therefore been looking for signaling molecules that respond to TGF-beta stimulation. In this pursuit they studied the heart cells of some 80 heart attack patients from whom tissue samples were taken during bypass operations. To their surprise, the signaling molecule interleukin 11 (IL 11) – which had previously been thought to inhibit connective tissue formation – proved to be the signaling molecule in which TGF-beta produces the greatest stimulation.

Interleukin 11 is specifically present in fibroblasts

“We were able to detect high RNA activity for IL 11 and its receptor in the fibroblasts from the heart biopsies,” says Professor Norbert Hübner, head of the MDC’s Genetics and Genomics of Cardiovascular Diseases research team. This was confirmed in animal studies: The heart tissue of IL 11-treated mice showed an increase in connective tissue deposits in the myocardium, while the inhibition of IL 11 activity by antibodies reduced the production of connective tissue proteins.

The researchers see these antibodies against IL 11 as suitable candidates for the development of an effective medication to prevent excessive connective tissue production. Another point in IL 11’s favor is where it is specifically found: In contrast to other signaling molecules, interleukin 11 is present almost exclusively in fibroblasts.

    The Max Delbrück Center for Molecular Medicine (MDC)

     

    The Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC) was founded in Berlin in 1992. It is named for the German-American physicist Max Delbrück, who was awarded the 1969 Nobel Prize in Physiology and Medicine. The MDC's mission is to study molecular mechanisms in order to understand the origins of disease and thus be able to diagnose, prevent and fight it better and more effectively. In these efforts the MDC cooperates with the Charité - Universitätsmedizin Berlin and the Berlin Institute of Health (BIH) as well as with national partners such as the German Center for Cardiovascular Research and numerous international research institutions. More than 1,600 staff and guests from nearly 60 countries work at the MDC, just under 1,300 of them in scientific research. The MDC is funded by the German Federal Ministry of Education and Research (90 percent) and the State of Berlin (10 percent), and is a member of the Helmholtz Association of German Research Centers. www.mdc-berlin.de

    Sebastian Schafer et al. (2017): “IL11 is a crucial determinant of cardiovascular fibrosis.” Nature. doi:10.1038/nature24676