Inhibition of N-type calcium channels in cardiac sympathetic neurons attenuates ventricular arrhythmogenesis in heart failure.
Action Potentials
Animals
Calcium
/ metabolism
Calcium Channels, N-Type
/ genetics
Calcium Signaling
Cells, Cultured
Disease Models, Animal
Heart
/ innervation
Heart Failure
/ genetics
Heart Rate
Male
RNA Interference
RNA, Small Interfering
/ genetics
Rats, Sprague-Dawley
Stellate Ganglion
/ metabolism
Sympathetic Fibers, Postganglionic
/ metabolism
Tachycardia, Ventricular
/ genetics
Ventricular Fibrillation
/ genetics
Cardiac sympathetic post-ganglionic neurons
Chronic heart failure
N-type calcium channel
Stellate ganglia
Ventricular arrhythmias
Journal
Cardiovascular research
ISSN: 1755-3245
Titre abrégé: Cardiovasc Res
Pays: England
ID NLM: 0077427
Informations de publication
Date de publication:
01 01 2021
01 01 2021
Historique:
received:
13
09
2019
revised:
13
11
2019
accepted:
21
01
2020
pubmed:
30
1
2020
medline:
7
10
2021
entrez:
30
1
2020
Statut:
ppublish
Résumé
Cardiac sympathetic overactivation is an important trigger of ventricular arrhythmias in patients with chronic heart failure (CHF). Our previous study demonstrated that N-type calcium (Cav2.2) currents in cardiac sympathetic post-ganglionic (CSP) neurons were increased in CHF. This study investigated the contribution of Cav2.2 channels in cardiac sympathetic overactivation and ventricular arrhythmogenesis in CHF. Rat CHF was induced by surgical ligation of the left coronary artery. Lentiviral Cav2.2-α shRNA or scrambled shRNA was transfected in vivo into stellate ganglia (SG) in CHF rats. Final experiments were performed at 14 weeks after coronary artery ligation. Real-time polymerase chain reaction and western blot data showed that in vivo transfection of Cav2.2-α shRNA reduced the expression of Cav2.2-α mRNA and protein in the SG in CHF rats. Cav2.2-α shRNA also reduced Cav2.2 currents and cell excitability of CSP neurons and attenuated cardiac sympathetic nerve activities (CSNA) in CHF rats. The power spectral analysis of heart rate variability (HRV) further revealed that transfection of Cav2.2-α shRNA in the SG normalized CHF-caused cardiac sympathetic overactivation in conscious rats. Twenty-four-hour continuous telemetry electrocardiogram recording revealed that this Cav2.2-α shRNA not only decreased incidence and duration of ventricular tachycardia/ventricular fibrillation but also improved CHF-induced heterogeneity of ventricular electrical activity in conscious CHF rats. Cav2.2-α shRNA also decreased susceptibility to ventricular arrhythmias in anaesthetized CHF rats. However, Cav2.2-α shRNA failed to improve CHF-induced cardiac contractile dysfunction. Scrambled shRNA did not affect Cav2.2 currents and cell excitability of CSP neurons, CSNA, HRV, and ventricular arrhythmogenesis in CHF rats. Overactivation of Cav2.2 channels in CSP neurons contributes to cardiac sympathetic hyperactivation and ventricular arrhythmogenesis in CHF. This suggests that discovering purely selective and potent small-molecule Cav2.2 channel blockers could be a potential therapeutic strategy to decrease fatal ventricular arrhythmias in CHF.
Identifiants
pubmed: 31995173
pii: 5717428
doi: 10.1093/cvr/cvaa018
pmc: PMC7797209
doi:
Substances chimiques
Cacna1b protein, rat
0
Calcium Channels, N-Type
0
RNA, Small Interfering
0
Calcium
SY7Q814VUP
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
137-148Subventions
Organisme : NHLBI NIH HHS
ID : R01 HL098503
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL137832
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL144146
Pays : United States
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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