Project Details
Projekt
P6: Stretch-Activated Ion Channels in Non-Myocytes Linking Cardiac Mechanics, Interstitial Remodelling, and Arrhythmogenesis
Applicants
Privatdozent Dr. Achim Lother; Dr. Remi Peyronnet
Subject Area
Cardiology, Angiology
Anatomy and Physiology
Cell Biology
Anatomy and Physiology
Cell Biology
Term
since 2026
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 564978926
Atrial fibrillation (AF) and heart failure, particularly with preserved ejection fraction, are two frequent and often co-existing cardiac disorders. Existing evidence links atrial remodelling and AF to neurohormonal signaling, e.g. via aldosterone. For instance, patients with primary hyperaldosteronism have a markedly higher risk of developing AF compared to those with essential hypertension. In addition to biochemical signals, haemodynamic alterations establish a bidirectional relationship between heart failure and AF, in which each condition promotes the development and progression of the other. Impaired diastolic function leads to elevated ventricular and atrial pressures and a decline in left atrial compliance - key features of atrial myopathy. These alterations in tissue mechanical properties primarily result from interstitial remodeling, particularly fibrosis. Fibrosis is especially detrimental, as it impairs myocardial mechanical function and creates a substrate for re-entrant electrical circuits - one of the central mechanisms sustaining AF. Despite its clinical relevance, the molecular mechanisms driving interstitial remodelling and fibrosis in the heart remain incompletely understood. Consequently, there are currently no effective strategies beyond blockade of neurohumoral signaling to slow, stop, or reverse these processes. In this context of mechanical overload and altered tissue mechanics, the role of mechanical factors in the perpetuation of atrial myopathy is gaining increasing attention. Non-myocytes, the main contributors to interstitial remodeling, are highly sensitive to changes in their mechanical environment through several mechanosensitive receptors, including stretch-activated ion channels. Among them, Piezo1 is one of the most expressed in most non-myocytes and has been strongly implicated in interstitial remodeling in various organs. We hypothesize that interstitial remodeling, once initiated, alters cell mechanical environment, which if mechanical overload persists, in turn further aggravates interstitial remodeling in a feed-forward vicious circle. In this project, we will study the role of Piezo1 in non-myocytes as regulator of cardiac fibrosis in ventricular diastolic dysfunction and AF. More specifically we aim to investigate the effect of Piezo1 in cardiac fibroblasts and endothelial cells, on interstitial remodelling and arrhythmogenesis in vivo. We propose to assess the effects of signaling, downstream of Piezo1, on the transcriptional regulation of interstitial fibrosis in vivo. We intend to determine how biophysical versus biochemical cues regulate Piezo1-mediated interstitial remodeling and arrhythmogenesis in vitro. And finally, we want to explore the potential of candidate regulators of interstitial remodeling, downstream of Piezo1, as therapeutic targets to prevent, slow down, or even reverse interstitial remodeling.
DFG Programme
Research Units
