Gq-mediated Arrhythmogenic Signaling and Mechanotransduction in Atrial Fibrillation

• Applicant: Privatdozent Dr. Felix Hohendanner, Ph.D., since 4/2024
• Subject Area: Cardiology, Angiology
• Term: since 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 497794268

Numerous pathological conditions promote atrial fibrillation through neurohumoral stimuli, many of which are mediated via receptors coupled to G-proteins of the Gq-family (Gq-proteins), like for instance the angiotensin II receptor type 1, the endothelin-1 receptor A, the M3 muscarinic acetylcholine receptor and the alpha-1 adrenergic receptor. In addition, mechanical stimuli are known to trigger and sustain atrial fibrillation, but the molecular mechanisms that link mechanical forces to arrhythmogenesis are incompletely understood. Of note, we have recently uncovered a central involvement of Gq-proteins in cellular mechanotransduction. However, even though abundant evidence points to a key role of Gq-proteins in atrial fibrillation, Gq-mediated signaling itself has not been specifically studied in this context. Interestingly, we found cardiomyocyte-specific Gq-deficiency to protect mice from atrial fibrillation in preliminary studies. Regarding a potential mechanism, it has to be considered that Gq-signaling results in downstream activation of type 2 IP3 receptors that have been shown to promote arrhythmogenic calcium release from the sarcoplasmatic reticulum resulting in delayed afterdepolarisations – a key pathomechanism of human atrial fibrillation. Indeed, in preliminary experiments of this project, we found arrhythmogenic calcium release events to be markedly reduced in atrial myocytes from Gq-deficient mice. Against this background we have established atrial stretch assays as well as a whole-heart volume-overload model to further dissect the putative role and mechanism of Gq-mediated arrhythmogenic signaling and mechanotransduction. With regard to potential therapeutic implications, we will validate key findings from electrophysiological in vitro and ex vivo studies in intact human right atrial preparations that we acquire from patients undergoing cardiac surgery.As the use of all currently approved antiarrhythmic drugs is limited by potentially life-threatening ventricular proarrhythmic effects, it is intriguing that IP3 receptor 2-mediated effects appear to be specific for atrial myocytes and are absent in ventricular myocytes. This renders the Gq-IP3-signaling pathway a promising and atrium-specific target for the treatment of atrial fibrillation. However, to date no therapeutic approach selectively targeting this pathway has been developed. Based on the novel concept of ligand-biased signaling, we have recently identified a biased angiotensin receptor ligand that selectively inhibits Gq-mediated signal transduction without interfering with other signaling pathways. Thus, our ultimate goal will be to define the antiarrhythmic efficacy and therapeutic potential of selective Gq-inhibition with this biased angiotensin receptor ligand in a murine in vivo-model of atrial fibrillation.

• DFG Programme: Research Grants
• Ehemaliger Antragsteller: Privatdozent Dr. Till Althoff, until 4/2024