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Paclitaxel mitigates structural alterations and cardiac conduction system defects in a mouse model of Hutchinson-Gilford progeria syndrome
- Source :
- Cardiovascular Research
- Publication Year :
- 2020
-
Abstract
- Aims 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. Methods and results 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. Conclusions 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.<br />Graphical Abstract
- Subjects :
- Male
Refractory Period, Electrophysiological
Physiology
Swine
Cardiac index
Action Potentials
Laminopathy
Afterdepolarization
Progerin
Progeria
Heart Rate
Tubulin
Myocytes, Cardiac
AcademicSubjects/MED00200
Cytoskeleton
Excitation Contraction Coupling
Cardiomyocytes
integumentary system
Lamin Type A
Electrophysiology
Cardiology
Swine, Miniature
Female
Electrical conduction system of the heart
Cardiology and Cardiovascular Medicine
Anti-Arrhythmia Agents
medicine.medical_specialty
Paclitaxel
Cardiac Electrophysiology and Arrhythmia
Heart Conduction System
Physiology (medical)
Internal medicine
Animal model of cardiovascular disease
Cardiac conduction
medicine
Repolarization
Animals
Genetic Predisposition to Disease
Lamin A/C
Hutchinson–Gilford progeria syndrome
business.industry
Arrhythmias, Cardiac
Original Articles
medicine.disease
Mice, Mutant Strains
Disease Models, Animal
Mutation
business
Subjects
Details
- ISSN :
- 17553245
- Volume :
- 118
- Issue :
- 2
- Database :
- OpenAIRE
- Journal :
- Cardiovascular research
- Accession number :
- edsair.doi.dedup.....6f24170b70fb89a7a0130672f81004c0