Paclitaxel mitigates structural alterations and cardiac conduction system defects in a mouse model of Hutchinson-Gilford progeria syndrome

Cardiovasc Res. 2022 Jan 29;118(2):503-516. doi: 10.1093/cvr/cvab055.

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.

Keywords: Animal model of cardiovascular disease; Cardiomyocytes; Electrophysiology; Hutchinson–Gilford progeria syndrome; Lamin A/C; Progerin.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Action Potentials / drug effects
  • Animals
  • Anti-Arrhythmia Agents / pharmacology*
  • Arrhythmias, Cardiac / drug therapy*
  • Arrhythmias, Cardiac / genetics
  • Arrhythmias, Cardiac / metabolism
  • Arrhythmias, Cardiac / physiopathology
  • Cytoskeleton / drug effects*
  • Cytoskeleton / metabolism
  • Cytoskeleton / pathology
  • Disease Models, Animal
  • Excitation Contraction Coupling / drug effects*
  • Female
  • Genetic Predisposition to Disease
  • Heart Conduction System / drug effects*
  • Heart Conduction System / metabolism
  • Heart Conduction System / physiopathology
  • Heart Rate / drug effects*
  • Lamin Type A / genetics
  • Lamin Type A / metabolism
  • Male
  • Mice
  • Mice, Mutant Strains
  • Mutation
  • Myocytes, Cardiac / drug effects*
  • Myocytes, Cardiac / metabolism
  • Myocytes, Cardiac / pathology
  • Paclitaxel / pharmacology*
  • Progeria / drug therapy*
  • Progeria / genetics
  • Progeria / metabolism
  • Progeria / physiopathology
  • Refractory Period, Electrophysiological / drug effects
  • Swine
  • Swine, Miniature
  • Tubulin / metabolism

Substances

  • Anti-Arrhythmia Agents
  • Lamin Type A
  • Lmna protein, mouse
  • Tubulin
  • Paclitaxel