G<sub>q</sub>-Mediated Arrhythmogenic Signaling Promotes Atrial Fibrillation
Background: Atrial fibrillation (AF) is promoted by various stimuli like angiotensin II, endothelin-1, epinephrine/norepinephrine, vagal activation, or mechanical stress, all of which activate receptors coupled to G-proteins of the Gα<sub>q</sub>/Gα<sub>11</sub>-family (G<...
| Main Authors: | , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2023-02-01
|
| Series: | Biomedicines |
| Subjects: | |
| Online Access: | https://www.mdpi.com/2227-9059/11/2/526 |
| _version_ | 1797622142814126080 |
|---|---|
| author | Felix Hohendanner Ashok Prabhu Nicola Wilck Verena Stangl Burkert Pieske Karl Stangl Till F. Althoff |
| author_facet | Felix Hohendanner Ashok Prabhu Nicola Wilck Verena Stangl Burkert Pieske Karl Stangl Till F. Althoff |
| author_sort | Felix Hohendanner |
| collection | DOAJ |
| description | Background: Atrial fibrillation (AF) is promoted by various stimuli like angiotensin II, endothelin-1, epinephrine/norepinephrine, vagal activation, or mechanical stress, all of which activate receptors coupled to G-proteins of the Gα<sub>q</sub>/Gα<sub>11</sub>-family (G<sub>q</sub>). Besides pro-fibrotic and pro-inflammatory effects, G<sub>q</sub>-mediated signaling induces inositol trisphosphate receptor (IP<sub>3</sub>R)-mediated intracellular Ca<sup>2+</sup> mobilization related to delayed after-depolarisations and AF. However, direct evidence of arrhythmogenic G<sub>q</sub>-mediated signaling is absent. Methods and results: To define the role of G<sub>q</sub> in AF, transgenic mice with tamoxifen-inducible, cardiomyocyte-specific Gα<sub>q</sub>/Gα<sub>11</sub>-deficiency (G<sub>q</sub>-KO) were created and exposed to intracardiac electrophysiological studies. Baseline electrophysiological properties, including heart rate, sinus node recovery time, and atrial as well as AV nodal effective refractory periods, were comparable in G<sub>q</sub>-KO and control mice. However, inducibility and mean duration of AF episodes were significantly reduced in G<sub>q</sub>-KO mice—both before and after vagal stimulation. To explore underlying mechanisms, left atrial cardiomyocytes were isolated from G<sub>q</sub>-KO and control mice and electrically stimulated to study Ca<sup>2+</sup>-mobilization during excitation–contraction coupling using confocal microscopy. Spontaneous arrhythmogenic Ca<sup>2+</sup> waves and sarcoplasmic reticulum content-corrected Ca<sup>2+</sup> sparks were less frequent in G<sub>q</sub>-KO mice. Interestingly, nuclear but not cytosolic Ca<sup>2+</sup> transient amplitudes were significantly decreased in G<sub>q</sub>-KO mice. Conclusion: G<sub>q</sub>-signaling promotes arrhythmogenic atrial Ca<sup>2+</sup>-release and AF in mice. Targeting this pathway, ideally using G<sub>q</sub>-selective, biased receptor ligands, may be a promising approach for the treatment and prevention of AF. Importantly, the atrial-specific expression of the G<sub>q</sub>-effector IP<sub>3</sub>R confers atrial selectivity mitigating the risk of life-threatening ventricular pro-arrhythmic effects. |
| first_indexed | 2024-03-11T09:07:08Z |
| format | Article |
| id | doaj.art-96a903d49b1b46918e50d6e65bccffb3 |
| institution | Directory Open Access Journal |
| issn | 2227-9059 |
| language | English |
| last_indexed | 2024-03-11T09:07:08Z |
| publishDate | 2023-02-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Biomedicines |
| spelling | doaj.art-96a903d49b1b46918e50d6e65bccffb32023-11-16T19:19:31ZengMDPI AGBiomedicines2227-90592023-02-0111252610.3390/biomedicines11020526G<sub>q</sub>-Mediated Arrhythmogenic Signaling Promotes Atrial FibrillationFelix Hohendanner0Ashok Prabhu1Nicola Wilck2Verena Stangl3Burkert Pieske4Karl Stangl5Till F. Althoff6Department of Cardiology and German Heart Center, Campus Virchow-Klinikum, Charité–University Medicine Berlin, Augustenburger Platz 1, 13353 Berlin, GermanyDepartment of Cardiology and German Heart Center, Campus Virchow-Klinikum, Charité–University Medicine Berlin, Augustenburger Platz 1, 13353 Berlin, GermanyDZHK (German Centre for Cardiovascular Research), Partner Site Berlin, 13316 Berlin, GermanyDZHK (German Centre for Cardiovascular Research), Partner Site Berlin, 13316 Berlin, GermanyDepartment of Cardiology and German Heart Center, Campus Virchow-Klinikum, Charité–University Medicine Berlin, Augustenburger Platz 1, 13353 Berlin, GermanyDZHK (German Centre for Cardiovascular Research), Partner Site Berlin, 13316 Berlin, GermanyDZHK (German Centre for Cardiovascular Research), Partner Site Berlin, 13316 Berlin, GermanyBackground: Atrial fibrillation (AF) is promoted by various stimuli like angiotensin II, endothelin-1, epinephrine/norepinephrine, vagal activation, or mechanical stress, all of which activate receptors coupled to G-proteins of the Gα<sub>q</sub>/Gα<sub>11</sub>-family (G<sub>q</sub>). Besides pro-fibrotic and pro-inflammatory effects, G<sub>q</sub>-mediated signaling induces inositol trisphosphate receptor (IP<sub>3</sub>R)-mediated intracellular Ca<sup>2+</sup> mobilization related to delayed after-depolarisations and AF. However, direct evidence of arrhythmogenic G<sub>q</sub>-mediated signaling is absent. Methods and results: To define the role of G<sub>q</sub> in AF, transgenic mice with tamoxifen-inducible, cardiomyocyte-specific Gα<sub>q</sub>/Gα<sub>11</sub>-deficiency (G<sub>q</sub>-KO) were created and exposed to intracardiac electrophysiological studies. Baseline electrophysiological properties, including heart rate, sinus node recovery time, and atrial as well as AV nodal effective refractory periods, were comparable in G<sub>q</sub>-KO and control mice. However, inducibility and mean duration of AF episodes were significantly reduced in G<sub>q</sub>-KO mice—both before and after vagal stimulation. To explore underlying mechanisms, left atrial cardiomyocytes were isolated from G<sub>q</sub>-KO and control mice and electrically stimulated to study Ca<sup>2+</sup>-mobilization during excitation–contraction coupling using confocal microscopy. Spontaneous arrhythmogenic Ca<sup>2+</sup> waves and sarcoplasmic reticulum content-corrected Ca<sup>2+</sup> sparks were less frequent in G<sub>q</sub>-KO mice. Interestingly, nuclear but not cytosolic Ca<sup>2+</sup> transient amplitudes were significantly decreased in G<sub>q</sub>-KO mice. Conclusion: G<sub>q</sub>-signaling promotes arrhythmogenic atrial Ca<sup>2+</sup>-release and AF in mice. Targeting this pathway, ideally using G<sub>q</sub>-selective, biased receptor ligands, may be a promising approach for the treatment and prevention of AF. Importantly, the atrial-specific expression of the G<sub>q</sub>-effector IP<sub>3</sub>R confers atrial selectivity mitigating the risk of life-threatening ventricular pro-arrhythmic effects.https://www.mdpi.com/2227-9059/11/2/526atrial fibrillationG-protein signalingIP<sub>3</sub> receptorsarrhythmogenic Ca<sup>2+</sup> releasebiased ligands |
| spellingShingle | Felix Hohendanner Ashok Prabhu Nicola Wilck Verena Stangl Burkert Pieske Karl Stangl Till F. Althoff G<sub>q</sub>-Mediated Arrhythmogenic Signaling Promotes Atrial Fibrillation Biomedicines atrial fibrillation G-protein signaling IP<sub>3</sub> receptors arrhythmogenic Ca<sup>2+</sup> release biased ligands |
| title | G<sub>q</sub>-Mediated Arrhythmogenic Signaling Promotes Atrial Fibrillation |
| title_full | G<sub>q</sub>-Mediated Arrhythmogenic Signaling Promotes Atrial Fibrillation |
| title_fullStr | G<sub>q</sub>-Mediated Arrhythmogenic Signaling Promotes Atrial Fibrillation |
| title_full_unstemmed | G<sub>q</sub>-Mediated Arrhythmogenic Signaling Promotes Atrial Fibrillation |
| title_short | G<sub>q</sub>-Mediated Arrhythmogenic Signaling Promotes Atrial Fibrillation |
| title_sort | g sub q sub mediated arrhythmogenic signaling promotes atrial fibrillation |
| topic | atrial fibrillation G-protein signaling IP<sub>3</sub> receptors arrhythmogenic Ca<sup>2+</sup> release biased ligands |
| url | https://www.mdpi.com/2227-9059/11/2/526 |
| work_keys_str_mv | AT felixhohendanner gsubqsubmediatedarrhythmogenicsignalingpromotesatrialfibrillation AT ashokprabhu gsubqsubmediatedarrhythmogenicsignalingpromotesatrialfibrillation AT nicolawilck gsubqsubmediatedarrhythmogenicsignalingpromotesatrialfibrillation AT verenastangl gsubqsubmediatedarrhythmogenicsignalingpromotesatrialfibrillation AT burkertpieske gsubqsubmediatedarrhythmogenicsignalingpromotesatrialfibrillation AT karlstangl gsubqsubmediatedarrhythmogenicsignalingpromotesatrialfibrillation AT tillfalthoff gsubqsubmediatedarrhythmogenicsignalingpromotesatrialfibrillation |