By stimulating the excessive buildup of connective tissue, signaling molecule contributes to heart disease
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) is one of the world’s leading biomedical research institutions. Max Delbrück, a Berlin native, was a Nobel laureate and one of the founders of molecular biology. At the MDC’s locations in Berlin-Buch and Mitte, researchers from some 60 countries analyze the human system – investigating the biological foundations of life from its most elementary building blocks to systems-wide mechanisms. By understanding what regulates or disrupts the dynamic equilibrium in a cell, an organ, or the entire body, we can prevent diseases, diagnose them earlier, and stop their progression with tailored therapies. Patients should benefit as soon as possible from basic research discoveries. The MDC therefore supports spin-off creation and participates in collaborative networks. It works in close partnership with Charité – Universitätsmedizin Berlin in the jointly run Experimental and Clinical Research Center (ECRC), the Berlin Institute of Health (BIH) at Charité, and the German Center for Cardiovascular Research (DZHK). Founded in 1992, the MDC today employs 1,600 people and is funded 90 percent by the German federal government and 10 percent by the State of Berlin.
Sebastian Schafer et al. (2017): “IL11 is a crucial determinant of cardiovascular fibrosis.” Nature. doi:10.1038/nature24676
