Paclitaxel mitigates structural alterations and cardiac conduction system defects in a mouse model of Hutchinson-Gilford progeria syndrome.
Action Potentials
/ drug effects
Animals
Anti-Arrhythmia Agents
/ pharmacology
Arrhythmias, Cardiac
/ drug therapy
Cytoskeleton
/ drug effects
Disease Models, Animal
Excitation Contraction Coupling
/ drug effects
Female
Genetic Predisposition to Disease
Heart Conduction System
/ drug effects
Heart Rate
/ drug effects
Lamin Type A
/ genetics
Male
Mice, Mutant Strains
Mutation
Myocytes, Cardiac
/ drug effects
Paclitaxel
/ pharmacology
Progeria
/ drug therapy
Refractory Period, Electrophysiological
/ drug effects
Swine
Swine, Miniature
Tubulin
/ metabolism
Animal model of cardiovascular disease
Cardiomyocytes
Electrophysiology
Hutchinson–Gilford progeria syndrome
Lamin A/C
Progerin
Journal
Cardiovascular research
ISSN: 1755-3245
Titre abrégé: Cardiovasc Res
Pays: England
ID NLM: 0077427
Informations de publication
Date de publication:
29 01 2022
29 01 2022
Historique:
received:
01
06
2020
revised:
11
11
2020
accepted:
09
02
2021
pubmed:
25
2
2021
medline:
3
3
2022
entrez:
24
2
2021
Statut:
ppublish
Résumé
Hutchinson-Gilford progeria syndrome (HGPS) is an ultrarare laminopathy caused by expression of progerin, a lamin A variant, also present at low levels in non-HGPS individuals. HGPS patients age and die prematurely, predominantly from cardiovascular complications. Progerin-induced cardiac repolarization defects have been described previously, although the underlying mechanisms are unknown. We conducted studies in heart tissue from progerin-expressing LmnaG609G/G609G (G609G) mice, including microscopy, intracellular calcium dynamics, patch-clamping, in vivo magnetic resonance imaging, and electrocardiography. G609G mouse cardiomyocytes showed tubulin-cytoskeleton disorganization, t-tubular system disruption, sarcomere shortening, altered excitation-contraction coupling, and reductions in ventricular thickening and cardiac index. G609G mice exhibited severe bradycardia, and significant alterations of atrio-ventricular conduction and repolarization. Most importantly, 50% of G609G mice had altered heart rate variability, and sinoatrial block, both significant signs of premature cardiac aging. G609G cardiomyocytes had electrophysiological alterations, which resulted in an elevated action potential plateau and early afterdepolarization bursting, reflecting slower sodium current inactivation and long Ca+2 transient duration, which may also help explain the mild QT prolongation in some HGPS patients. Chronic treatment with low-dose paclitaxel ameliorated structural and functional alterations in G609G hearts. Our results demonstrate that tubulin-cytoskeleton disorganization in progerin-expressing cardiomyocytes causes structural, cardiac conduction, and excitation-contraction coupling defects, all of which can be partially corrected by chronic treatment with low dose paclitaxel.
Identifiants
pubmed: 33624748
pii: 6149085
doi: 10.1093/cvr/cvab055
pmc: PMC8803078
doi:
Substances chimiques
Anti-Arrhythmia Agents
0
Lamin Type A
0
Lmna protein, mouse
0
Tubulin
0
Paclitaxel
P88XT4IS4D
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
503-516Subventions
Organisme : NIA NIH HHS
ID : P30 AG024824
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL122352
Pays : United States
Informations de copyright
© The Author(s) 2021. Published by Oxford University Press on behalf of the European Society of Cardiology.
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