Paclitaxel mitigates structural alterations and cardiac conduction system defects in a mouse model of Hutchinson–Gilford progeria syndrome. Issue 2 (24th February 2021)

• Record Type: Journal Article
• Authors: Macías, Álvaro; Díaz-Larrosa, J Jaime; Blanco, Yaazan; Fanjul, Víctor; González-Gómez, Cristina; Gonzalo, Pilar; Andrés-Manzano, María Jesús; da Rocha, Andre Monteiro; Ponce-Balbuena, Daniela; Allan, Andrew; Filgueiras-Rama, David; Jalife, José; Andrés, Vicente
• Is Part Of: Cardiovascular research. Volume 118:Issue 2(2022)
• Page Start: 503
• Page End: 516
• Publication Date: 2021-02-24
• Subjects: Hutchinson–Gilford progeria syndrome -- Animal model of cardiovascular disease -- Electrophysiology -- Lamin A/C -- Progerin -- Cardiomyocytes; Cardiovascular system -- Diseases -- Periodicals; Cardiovascular system -- Periodicals; 616.1
• DOI: 10.1093/cvr/cvab055
• Languages: English
• ISSNs: 0008-6363

Abstract

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 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. Graphical Abstract: