Stretch-dependent AT1 and M2 receptor signaling in cardiomyocytes and cardiac arrhythmia mechanisms

• Applicant: Professor Dr. Philipp Sasse
• Subject Area: Anatomy and Physiology
• Term: since 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 551378170

During contraction and relaxation, the heart undergoes cyclic stretch and acute variation of diastolic stretch physiologically regulates cardiac output whereas chronic stretch may induce cardiac pathologies leading to ventricular arrhythmia and atrial fibrillation with high morbidity and mortality. G-protein coupled receptors (GPCRs) play a major role in cardiac disease progression including the Angiotensin II receptor type 1 (AT1R) in the ventricle and the muscarinic receptor type 2 (M2R) in the atria. In the last decade, a stretch sensitivity of several GPCRs including the AT1R, but not the M2R, was discovered. Moreover, several pathological situations such as pulmonary embolism leading to atrial pressure-overload or infarction leading to areas with high stretch in the border zone are associated with the new-onset of atrial or ventricular arrhythmia, but little is known about the involvement of acute stretch-dependent GPCR signaling. Thus, in this project, we aim to investigate acute stretch-induced effects of AT1R and M2R in cardiomyocytes and their consequences for ventricular arrhythmia and atrial fibrillation mechanisms. To achieve these objectives, we will investigate the differences in agonist and stretch-induced AT1R downstream signaling in beating human cardiomyocytes as well as their involvement in ventricular arrhythmia mechanisms in isolated mouse hearts, and test the ability of AT1R blockers to modulate potential pathological stretch effects or arrestin-biased agonists, which have been shown to be cardioprotective in heart failure. Because M2R-induced activation of potassium channels as well as acute and chronic stretch of the atria promote atrial fibrillation, we will investigate the differences in pharmacological and stretch-induced M2R activation in atrial cardiomyocytes, the consequences for initiation and maintenance of atrial fibrillation in mouse hearts, and try to identify antagonists which can selectively modulate stretch-induced M2R activation of potassium channels. Altogether, we hope to provide stretch-induced AT1R and M2R biased signaling as novel cardiac arrhythmia mechanism and try to identify compounds specifically interfering with stretch-induced pro-arrhythmic effects as a new therapeutic concept.

• DFG Programme: Research Grants