Co-expression of calcium and hERG potassium channels reduces the incidence of proarrhythmic events.
Action Potentials
Arrhythmias, Cardiac
/ genetics
Calcium Channels, L-Type
/ genetics
Cells, Cultured
Databases, Genetic
ERG1 Potassium Channel
/ genetics
Heart Rate
Humans
Induced Pluripotent Stem Cells
/ metabolism
Models, Cardiovascular
Myocytes, Cardiac
/ metabolism
RNA-Seq
Signal Transduction
Time Factors
Calcium channels
Cardiac arrhythmia
Computational modelling
Gene expression
Potassium channels
Journal
Cardiovascular research
ISSN: 1755-3245
Titre abrégé: Cardiovasc Res
Pays: England
ID NLM: 0077427
Informations de publication
Date de publication:
29 08 2021
29 08 2021
Historique:
received:
16
06
2020
revised:
25
08
2020
accepted:
17
09
2020
pubmed:
2
10
2020
medline:
25
2
2022
entrez:
1
10
2020
Statut:
ppublish
Résumé
Cardiac electrical activity is extraordinarily robust. However, when it goes wrong it can have fatal consequences. Electrical activity in the heart is controlled by the carefully orchestrated activity of more than a dozen different ion conductances. While there is considerable variability in cardiac ion channel expression levels between individuals, studies in rodents have indicated that there are modules of ion channels whose expression co-vary. The aim of this study was to investigate whether meta-analytic co-expression analysis of large-scale gene expression datasets could identify modules of co-expressed cardiac ion channel genes in human hearts that are of functional importance. Meta-analysis of 3653 public human RNA-seq datasets identified a strong correlation between expression of CACNA1C (L-type calcium current, ICaL) and KCNH2 (rapid delayed rectifier K+ current, IKr), which was also observed in human adult heart tissue samples. In silico modelling suggested that co-expression of CACNA1C and KCNH2 would limit the variability in action potential duration seen with variations in expression of ion channel genes and reduce susceptibility to early afterdepolarizations, a surrogate marker for proarrhythmia. We also found that levels of KCNH2 and CACNA1C expression are correlated in human-induced pluripotent stem cell-derived cardiac myocytes and the levels of CACNA1C and KCNH2 expression were inversely correlated with the magnitude of changes in repolarization duration following inhibition of IKr. Meta-analytic approaches of multiple independent human gene expression datasets can be used to identify gene modules that are important for regulating heart function. Specifically, we have verified that there is co-expression of CACNA1C and KCNH2 ion channel genes in human heart tissue, and in silico analyses suggest that CACNA1C-KCNH2 co-expression increases the robustness of cardiac electrical activity.
Identifiants
pubmed: 33002116
pii: 5917019
doi: 10.1093/cvr/cvaa280
pmc: PMC8785951
doi:
Substances chimiques
CACNA1C protein, human
0
Calcium Channels, L-Type
0
ERG1 Potassium Channel
0
KCNH2 protein, human
0
Banques de données
Dryad
['10.5061/dryad.612jm640k']
Types de publication
Journal Article
Meta-Analysis
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
2216-2227Subventions
Organisme : NIMH NIH HHS
ID : R01 MH113005
Pays : United States
Organisme : National Institutes of Health (NIH)
ID : R01LM012736
Organisme : National Health and Medical Research Council (NHMRC)
ID : App1116948
Informations de copyright
Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2020. For permissions, please email: journals.permissions@oup.com.
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