Heart cells last a lifetime
The development of the disease is closely linked to the special nature of heart cells, which are also known as cardiomyocytes. While many other cells in the body divide frequently to repair damaged tissue, this process occurs to only a very limited extent in the heart muscle. Far fewer than 50 percent of cardiomyocytes divide once in a lifetime, and most of them endure for the individual’s lifespan. “Seeing as they hardly ever reproduce, the heart cells are dependent on good maintenance,” explains Abdellatif. “However, the autophagy of cardiomyocytes decreases with age. Obesity, high blood pressure and kidney disease are additional risk factors.” Cell aging, reduced autophagy, chronic inflammation and other factors cause heart cells to die, and more and more connective tissue is deposited in the heart muscle. This results in stiffness and the heart's reduced capability to fill with blood.
Abdellatif has already conducted research on a number of active substances that can positively influence autophagy in the heart cells, including the cellular substance spermidine or nicotinamide, also known as vitamin B3. “There are promising results with these substances,” explains the cardiologist. “But the problem is that they all interfere with processes in the cell or even the cell nucleus in order to trigger autophagy. In the process, they can also trigger effects that are not specific or desirable, which could make it difficult to translate the findings into a therapy.”
Starting points outside the heart cells
For this reason, Abdellatif and his team are seeking to break completely new ground in the “Ener-LIGHT” project. “We are looking in the bloodstream outside the cells for factors that influence autophagy in the heart cells,” he notes. “If we succeed in influencing extracellular factors of this nature, we will no longer need to introduce active substances into the cell – and this could greatly improve the tolerability of therapeutic interventions.” In addition, the researchers are scanning the blood constituents for biomarkers that can supply information about the condition, autophagy and metabolism of heart cells.
Combining a preclinical and clinical approach in the project, the research team is using a variety of methods to discover the desirable “autophagy-modulating targets”, develop suitable active substances and test them. The international teams contribute their multidisciplinary expertise in the fields of experimental and clinical cardiology, cell biology and immunology. Blood and heart tissue samples are analyzed for data and compared with that of healthy patients. Molecular biology tools are used to produce drug prototypes, which are then tested in cell cultures and animal models.
Promising results
Initial findings have already led to the identification of a target candidate that could be used to address cardiac cell cleansing. “A certain protein that binds to activated fatty acids and plays an important role in cellular energy supply has revealed itself as a promising agent,” reports Abdellatif. “If we block the protein, with antibodies or genetic deactivation, for instance, it is possible to reactivate autophagy in the heart. We are currently investigating whether this mechanism actually prevents the development of heart failure with preserved ejection fraction.”
If the research is successful, this would also be good news for the treatment of other conditions in which autophagy plays a role. Abdellatif makes special mention of the area of neurodegenerative diseases: “Like heart cells, neurons can hardly be replaced because they lack the ability to divide,” he says. “That's why hopes run high in this respect that activating autophagy can also delay diseases such as dementia.” On the other hand, the findings could also open up new avenues of research into metabolic diseases and certain forms of obesity. The hope is that the activation of cellular quality control can make a significant contribution to healthier aging.
