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

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. Mouse G609G 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 result 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 of paclitaxel.

Molecular and Cellular Mechanisms Driving Cardiovascular Disease in Hutchinson-Gilford Progeria Syndrome: Lessons Learned from Animal Models

“…Using this model, these authors provided the first in vivo evidence that antisense morpholino-based therapy to prevent the pathogenic Lmna splicing might be viable for HGPS. Homozygous Lmna G609G/G609G mice express progerin, lamin C, and residual levels of lamin A and show many HGPS features, including failure to thrive, bone defects, loss of fat deposits, bradycardia, prolonged QRS waves (indicating altered heart ventricular depolarization), and premature death [ 45 , 49 , 52 ]. Lmna G609G/G609G cardiomyocytes have structural, conduction, and excitation-contraction coupling defects, all of which can be partially corrected by chronic treatment with the microtubule-stabilizing drug paclitaxel [ 49 ].…”

“…Homozygous Lmna G609G/G609G mice express progerin, lamin C, and residual levels of lamin A and show many HGPS features, including failure to thrive, bone defects, loss of fat deposits, bradycardia, prolonged QRS waves (indicating altered heart ventricular depolarization), and premature death [ 45 , 49 , 52 ]. Lmna G609G/G609G cardiomyocytes have structural, conduction, and excitation-contraction coupling defects, all of which can be partially corrected by chronic treatment with the microtubule-stabilizing drug paclitaxel [ 49 ]. Vascular alterations include VSMC depletion in the medial layer of the aorta and other arteries, collagen and proteoglycan accumulation in the aortic media, reduced elastin fiber undulations, and increased vessel stiffness assessed by wire and pressure myography [ 45 , 51 , 55 , 56 , 65 ].…”

Dual Dysfunction of Kir2.1 Underlies Conduction and Excitation-Contraction Coupling Defects Promoting Arrhythmias in a Mouse Model of Andersen-Tawil Syndrome Type 1

“…The copyright holder for this preprint this version posted June 17, 2021. ; https://doi.org/10.1101/2021.06.17.448833 doi: bioRxiv preprint Calcium dynamics assays. Cytosolic Ca 2+ was monitored according to previously described protocols [56][57][58] .…”

“…Immunofluorescence. Isolated cardiomyocytes.-Cells were stained as described previously 56 . Additional details are presented in the Expanded Methods section of the Supplemental Material.…”

“…Calcium dynamics assays. Cytosolic Ca 2+ was monitored according to previously described protocols [56][57][58] .…”