Cytoskeletal disarray increases arrhythmogenic vulnerability during sympathetic stimulation in a model of hypertrophic cardiomyopathy.

Autor: Cserne Szappanos H; School of Human Sciences, University of Western Australia, Crawley, WA, Australia., Viola HM; School of Human Sciences, University of Western Australia, Crawley, WA, Australia., Ito DW; Department of Physiology and Membrane Biology, University of California, Davis, CA, USA., Lim S; Agnes Ginges Centre for Molecular Cardiology, Centenary Institute, Sydney, Australia.; Sydney Medical School, University of Sydney, Sydney, Australia., Mangala M; Victor Chang Cardiac Research Institute, Sydney, NSW, Australia., Holliday M; Agnes Ginges Centre for Molecular Cardiology, Centenary Institute, Sydney, Australia.; Sydney Medical School, University of Sydney, Sydney, Australia., Barratt Ross S; Agnes Ginges Centre for Molecular Cardiology, Centenary Institute, Sydney, Australia.; Sydney Medical School, University of Sydney, Sydney, Australia., Semsarian C; Agnes Ginges Centre for Molecular Cardiology, Centenary Institute, Sydney, Australia.; Sydney Medical School, University of Sydney, Sydney, Australia.; Department of Cardiology, Royal Prince Alfred Hospital, Sydney, Australia., Hill A; Victor Chang Cardiac Research Institute, Sydney, NSW, Australia., Dixon RE; Department of Physiology and Membrane Biology, University of California, Davis, CA, USA., Hool LC; School of Human Sciences, University of Western Australia, Crawley, WA, Australia. livia.hool@uwa.edu.au.; Victor Chang Cardiac Research Institute, Sydney, NSW, Australia. livia.hool@uwa.edu.au.
Jazyk: angličtina
Zdroj: Scientific reports [Sci Rep] 2023 Jul 12; Vol. 13 (1), pp. 11296. Date of Electronic Publication: 2023 Jul 12.
DOI: 10.1038/s41598-023-38296-2
Abstrakt: Familial hypertrophic cardiomyopathy (FHC) patients are advised to avoid strenuous exercise due to increased risk of arrhythmias. Mice expressing the human FHC-causing mutation R403Q in the myosin heavy chain gene (MYH6) recapitulate the human phenotype, including cytoskeletal disarray and increased arrhythmia susceptibility. Following in vivo administration of isoproterenol, mutant mice exhibited tachyarrhythmias, poor recovery and fatigue. Arrhythmias were attenuated with the β-blocker atenolol and protein kinase A inhibitor PKI. Mutant cardiac myocytes had significantly prolonged action potentials and triggered automaticity due to reduced repolarization reserve and connexin 43 expression. Isoproterenol shortened cycle length, and escalated electrical instability. Surprisingly isoproterenol did not increase Ca V 1.2 current. We found alterations in Ca V 1.2-β1 adrenergic receptor colocalization assessed using super-resolution nanoscopy, and increased Ca V 1.2 phosphorylation in mutant hearts. Our results reveal for the first time that altered ion channel expression, co-localization and β-adrenergic receptor signaling associated with myocyte disarray contribute to electrical instability in the R403Q mutant heart.
(© 2023. The Author(s).)
Databáze: MEDLINE
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