The cardiac role of Piezo1

• Applicants: Professor Dr. Andreas Deußen; Professor Dr. Michael Mederos y Schnitzler
• Subject Area: Anatomy and Physiology ; Pharmacology
• Term: since 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 503157935

Cardiovascular diseases are responsible for more than 40% of all deaths in Germany. Heart failure as a result of cardiac insufficiency is a frequent cause of death. In order to understand the pumping capacity of the heart, the connection between the processes of cardiac muscle excitation, mechanical force generation, energy supply and metabolism is of central importance. The mechanosensitive cation channel Piezo1, which is expressed in cardiomyocytes, has been known for a few years. The significance of Piezo1 for the connection between cardiac excitation and cardiac mechanics is largely unclear. This research project aims to elucidate the functional importance of Piezo1 in the heart with regard to the electro-mechanical and mechano-electrical coupling as well as for the cardiac muscle metabolism. For this purpose, we generated mice with a conditional cardiomyocyte-specific knock down of Piezo1, which allows the downregulation of Piezo1 expression in the adult heart. Preliminary findings indicate that the induction of the knock down of Piezo1 in cardiomyocytes leads to a decrease in stroke volume and pumping capacity of the heart suggesting an important role of Piezo1 for the regulation of the heart function.In this research project a detailed phenotyping of the knock down of Piezo1 regarding cellular and subcellular localization, excitation, calcium homeostasis, metabolism and contraction behavior from the subcellular level to the whole organism will be carried out in order to clarify the function of Piezo1 in cardiomyocytes. For this purpose, examinations using non-invasive cardiac echocardiography and ECG will be used to quantify possible perturbations of the excitation and of the regional heart muscle function in vivo. In addition, other functional parameters of the heart such as ventricular pressure, cardiac muscle contractility, coronary perfusion and oxygen consumption as well as expression parameters on the RNA and protein level will be examined. Targeted and untargeted metabolomics studies will be performed to objectify a possible influence of Piezo1 on metabolic homeostasis. Using transverse tissue slices of the heart, we will examine the stretch dependency of the contraction force. On the cellular level the importance of Piezo1 for the calcium homeostasis, the muscle action potential and for the mechano-electrical coupling will be analyzed by applying fluorimetric calcium and patch-clamp measurements. In addition, the sarcolemmal localization of Piezo1 will be determined using combined STED-atomic force microscopy. Moreover, endogenous compensation mechanisms for the impaired heart function induced by Piezo1 knock down will be analyzed. The elucidation of the physiological and pathophysiological role of Piezo1 for cardiac function could open up new therapeutic options for the treatment of heart failure.

• DFG Programme: Research Grants