| Title: |
TNNI3K delays atrioventricular conduction and reduces connexin-45 gap junctional coupling |
| Authors: |
Pham, C; Podliesna, S; Verkerk, AO; Wolswinkel, R; Munoz-Martin, N; Veldkamp, MW; Beekman, L; Wilde, LMW; Remme, CA; Bezzina, CR; Lodder, EM |
| Source: |
EP Europace ; volume 24, issue Supplement_1 ; ISSN 1099-5129 1532-2092 |
| Publisher Information: |
Oxford University Press (OUP) |
| Publication Year: |
2022 |
| Description: |
Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): The Dutch Research Council (NWO Talent Scheme) Introduction Cardiac conduction delay is the main substrate for triggering arrhythmias. Hence, prolongation of the PR interval on the electrocardiogram (ECG) is a strong predictor of atrial fibrillation, the most common cardiac arrhythmia. In previous research, cardiac troponin I-interacting kinase (TNNI3K) has been identified as a regulator of the PR interval. Various inbred mouse strains showed a correlation between Tnni3k expression levels and PR interval durations. Additionally, transgenic mice overexpressing hTNNI3K presented an extreme PR interval prolongation. Objective This study aims to unravel the mechanism underlying TNNI3K-driven PR interval prolongation. Methods ECG parameters were recorded in mice expressing physiological levels of Tnni3k (congenic), overexpressing hTNNI3K (TNNI3Ktg), or overexpressing kinase-dead hTNNI3K (TNNI3K-KDtg) and were compared to low-Tnni3k expressing DBA/2J control mice. Atrioventricular (AV) conduction was measured in Langendorff-perfused isolated hearts by electrical mapping. Cellular electrophysiology and conductance were measured using the (dual) patch-clamp technique. AV nodal collagen levels were identified by Pico Sirius Red staining. Candidate interactors were identified by immunoprecipitation of transfected HEK293A cell lysates. In stable HeLa-Connexin 45 (Cx45) cell lines expressing TNNI3K, Cx45 protein expression and phosphorylation levels were investigated by Western blot. Localisation of Cx45 was characterised by immunofluorescence. Results At six weeks of age, congenic and TNNI3Ktg mice show a 17% and 35% prolonged PR interval duration, respectively. Nonetheless, the PR interval of TNNI3K-KDtg mice did not change. Electrical mapping experiments on TNNI3Ktg mouse hearts show a corresponding AV conduction delay, which was neither driven by changes in cellular atrial cardiomyocyte ... |
| Document Type: |
article in journal/newspaper |
| Language: |
English |
| DOI: |
10.1093/europace/euac053.621 |
| Availability: |
https://doi.org/10.1093/europace/euac053.621; https://academic.oup.com/europace/article-pdf/24/Supplement_1/euac053.621/43770312/euac053.621.pdf |
| Rights: |
https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model |
| Accession Number: |
edsbas.486D2504 |
| Database: |
BASE |