Cardiomyocyte-specific loss of plasma membrane calcium ATPase 1 impacts cardiac rhythm and is associated with ventricular repolarisation dysfunction.



Wilson, Claire ORCID: 0000-0003-0456-1350, Stafford, Nicholas, Zi, Min, Chelu, Alexandru, Niort, Barbara C, Li, Yatong, Baudoin, Florence, Prehar, Sukhpal, Trafford, Andrew W ORCID: 0000-0002-2770-445X and Cartwright, Elizabeth J ORCID: 0000-0002-6836-7795
(2022) Cardiomyocyte-specific loss of plasma membrane calcium ATPase 1 impacts cardiac rhythm and is associated with ventricular repolarisation dysfunction. Journal of molecular and cellular cardiology, 172. 41 - 51.

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Abstract

Plasma membrane calcium ATPase 1 (PMCA1, Atp2b1) is emerging as a key contributor to cardiac physiology, involved in calcium handling and myocardial signalling. In addition, genome wide association studies have associated PMCA1 in several areas of cardiovascular disease including hypertension and myocardial infarction. Here, we investigated the role of PMCA1 in basal cardiac function and heart rhythm stability. Cardiac structure, heart rhythm and arrhythmia susceptibility were assessed in a cardiomyocyte-specific PMCA1 deletion (PMCA1<sup>CKO</sup>) mouse model. PMCA1<sup>CKO</sup> mice developed abnormal heart rhythms related to ventricular repolarisation dysfunction and displayed an increased susceptibility to ventricular arrhythmias. We further assessed the levels of cardiac ion channels using qPCR and found a downregulation of the voltage-dependent potassium channels, K<sub>v</sub>4.2, with a corresponding reduction in the transient outward potassium current which underlies ventricular repolarisation in the murine heart. The changes in heart rhythm were found to occur in the absence of any structural cardiomyopathy. To further assess the molecular changes occurring in PMCA1<sup>CKO</sup> hearts, we performed proteomic analysis. Functional characterisation of differentially expressed proteins suggested changes in pathways related to metabolism, protein-binding, and pathways associated cardiac function including β-adrenergic signalling. Together, these data suggest an important role for PMCA1 in basal cardiac function in relation to heart rhythm control, with reduced cardiac PMCA1 expression resulting in an increased risk of arrhythmia development.

Item Type: Article
Divisions: Faculty of Health and Life Sciences
Faculty of Health and Life Sciences > Institute of Systems, Molecular and Integrative Biology
Depositing User: Symplectic Admin
Date Deposited: 22 Aug 2022 09:11
Last Modified: 05 Oct 2022 19:02
DOI: 10.1016/j.yjmcc.2022.07.011
Open Access URL: https://doi.org/10.1016/j.yjmcc.2022.07.011
URI: https://livrepository.liverpool.ac.uk/id/eprint/3161960