The impact of oxidative stress on titin oxidation and titin-based myocardial stiffness
Over the last decade our research has focussed on understanding the mechanisms that underlie diastolic stiffness of the heart. A better understanding of the biological determinants of diastolic stiffness is of major clinical importance, as diastolic dysfunction is a hallmark in heart failure with preserved ejection fraction (HFpEF). This form of heart disease now accounts for over half of all cases of heart failure (HF) in developed countries. In terms of abnormal diastolic left ventricular diastolic (LV) function, HFpEF is characterised by impaired relaxation and increased diastolic stiffness. Efforts to develop broad HFpEF treatments have been disappointing, and it now appears that the development of tailored, personalized therapeutic strategies may be required to effectively treat distinct HFpEF phenotypes. A major element of diastolic stiffness is the specific state of the giant protein titin. A primary aim of our research in recent years has been to understand how titin modifications, including isoform transitions, phosphorylation and S-glutathionylation, affect myocardial stiffness. An exciting new development in this field has been the realization that co-morbidities common to HFpEF promote a systemic inflammatory state. The consequences of chronic inflammation include endothelial dysfunction, reactive oxygen species (ROS) production, nitrosative stress, and depressed nitric oxide (NO) bioavailability. The ensuing modulation of specific redox-sensitive signal transduction pathways results in certain modifications, which may then result in a decrease in NO bioavailability, leading to imbalances in several important signalling pathways involved in titin modifications, thus causing altered titin phosphorylation and oxidation (such as S-glutathionylation). The main goal of the current proposal is to unravel the redox-related mechanisms controlling titin-based stiffness and thereby diastolic stiffness, opening the way to the development of novel potential HFpEF treatments.
Ruhr-Universität Bochum: Dr. Nazha Hamdani, Medizinische Fakultät
Fördermittel: 50.000,00 Euro
Dr. Nazha Hamdani
Abteilung für Kardiovaskuläre Physiologie