Journal
CARDIOVASCULAR RESEARCH
Volume 118, Issue 2, Pages 503-516Publisher
OXFORD UNIV PRESS
DOI: 10.1093/cvr/cvab055
Keywords
Hutchinson-Gilford progeria syndrome; Animal model of cardiovascular disease; Electrophysiology; Lamin A; C; Progerin; Cardiomyocytes
Categories
Funding
- Spanish Ministerio de Ciencia e Innovacion (MCIN) [SAF2016-79490-R, PID2019-108489RBI00]
- Instituto de Salud Carlos III (ISCIII) [AC17/00067]
- European Regional Development Fund/Fondo Europeo de Desarrollo Regional (ERDF/FEDER, 'Una manera de hacer Europa')
- Progeria Research Foundation [PRF 2019-77]
- National Heart, Lung, and Blood Institute [HL122352]
- CNIC 'Severo Ochoa' intramural competitive grant
- Fondos FEDER, Madrid, Spain
- Spanish MCIN [SAF2016-80324-R]
- ISCIII [AC17/00053]
- MCIN
- ISCIII
- Pro CNIC Foundation
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This study found that heart tissue from Hutchinson-Gilford progeria syndrome (HGPS) patients has structural and electrophysiological defects, including disruption of the t-tubular system, shortened sarcomeres, bradycardia, and atrio-ventricular conduction abnormalities. Chronic treatment with low-dose paclitaxel partially corrected these abnormalities.
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 Lmna(G609G/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.
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