Mechanical Triggers to Programmed Cell Death in Cardiomyocytes – and how to prevent their Action in Failing Hearts
- Siegfried LABEIT, University of Heidelberg, Mannheim (Germany)
- Hendrikus GRANZIER, University of Arizona, Tucson (USA)
- Ralph KNOELL, Karolinska Institutet, Stockholm (Sweden)
- Olga MAYANS, University of Konstanz (Germany)
- Isabelle RICHARD, Généthon, Evry (France)
- Ju CHEN, UCSD, La Jolla, California (USA)
- H. Lee SWEENEY, University of Pennsylvania, Philadelphia (USA)
All types of heart failure (HF) show a progressive loss of cardiac myocytes—heart muscle cells– by cell death (apoptosis). It appears that the heart, exposed to lifelong cycles of stretch and release, loses its capacity to regenerate over time. This proposal focuses on mechanisms linking mechanical stress to apoptosis in cardiomyocytes, a phenomenon known as mechanoptosis. The members of this network argue that mechanoptosis is an important determinant of heart failure, and that by preventing this process, cardiomyocytes can be preserved and cardiac function maintained. They plan to address this problem by focusing on mechanical failure of the titin cytoskeleton as a trigger of apoptosis.
Recent findings strongly indicate that cell loss is a leading primary pathological mechanism in HF driven by changes in the titin filament, a giant protein that contributes to the elasticity of the heart. Elasticity, in turn, helps to determine the conditions under which the heart fills with blood during diastole, the period in the cardiac cycle when the heart is not actively pumping blood. A loss of elasticity is associated with diastolic heart failure. A recently published genetic study identified a mutation in titin as the cause of arrythmogenic cardiomyopathy, a primary disease of the heart muscle caused by a breakdown of healthy myocardium.
This network is tightly focused on the role of titin mediated stretch as a mechanical trigger of cardiomyocyte apoptosis. The program brings together an interdisciplinary team of world-leading experts who will work to identify the cellular mechanisms underlying progressive cytoskeletal pathologies in HF. Transgenic mouse models with genetically altered titin compliances will be examined, and the network has the ability to transition from mouse to large mammal studies in the case of promising gene candidates. Furthermore, the network will support the development of innovative therapies for heart failure by identifying plausible targets for regenerative/protective therapy to prevent cardiomyocyte death in the setting of disease.