Please use this identifier to cite or link to this item:
Title: Cardiac electrical defects in progeroid mice and Hutchinson-Gilford progeria syndrome patients with nuclear lamina alterations.
Authors: Rivera-Torres, José
Calvo, Conrado J
Llach, Anna
Guzmán-Martínez, Gabriela
Caballero, Ricardo
González-Gómez, Cristina
Jiménez-Borreguero, Luis J
Guadix, Juan A
Osorio, Fernando G
López-Otín, Carlos
Herraiz-Martínez, Adela
Cabello, Nuria
Vallmitjana, Alex
Benítez, Raul
Gordon, Leslie B
Jalife, José
Pérez-Pomares, José M
Tamargo, Juan
Delpón, Eva
Hove-Madsen, Leif
Filgueiras-Rama, David
Andrés, Vicente
Keywords: Hutchinson–Gilford progeria syndrome;calcium handling;connexin43;prelamin A;progerin
metadata.dc.subject.mesh: Adolescent
Arrhythmias, Cardiac
Cardiac Conduction System Disease
Child, Preschool
Connexin 43
Membrane Proteins
Mice, Inbred C57BL
Mice, Knockout
Nuclear Lamina
Sarcoplasmic Reticulum
Young Adult
Issue Date: 31-Oct-2016
Abstract: Hutchinson-Gilford progeria syndrome (HGPS) is a rare genetic disease caused by defective prelamin A processing, leading to nuclear lamina alterations, severe cardiovascular pathology, and premature death. Prelamin A alterations also occur in physiological aging. It remains unknown how defective prelamin A processing affects the cardiac rhythm. We show age-dependent cardiac repolarization abnormalities in HGPS patients that are also present in the Zmpste24-/- mouse model of HGPS. Challenge of Zmpste24-/- mice with the β-adrenergic agonist isoproterenol did not trigger ventricular arrhythmia but caused bradycardia-related premature ventricular complexes and slow-rate polymorphic ventricular rhythms during recovery. Patch-clamping in Zmpste24-/- cardiomyocytes revealed prolonged calcium-transient duration and reduced sarcoplasmic reticulum calcium loading and release, consistent with the absence of isoproterenol-induced ventricular arrhythmia. Zmpste24-/- progeroid mice also developed severe fibrosis-unrelated bradycardia and PQ interval and QRS complex prolongation. These conduction defects were accompanied by overt mislocalization of the gap junction protein connexin43 (Cx43). Remarkably, Cx43 mislocalization was also evident in autopsied left ventricle tissue from HGPS patients, suggesting intercellular connectivity alterations at late stages of the disease. The similarities between HGPS patients and progeroid mice reported here strongly suggest that defective cardiac repolarization and cardiomyocyte connectivity are important abnormalities in the HGPS pathogenesis that increase the risk of arrhythmia and premature death.
metadata.dc.identifier.doi: 10.1073/pnas.1603754113
Appears in Collections:Producción 2020

Files in This Item:
There are no files associated with this item.

This item is protected by original copyright

Except where otherwise noted, Items on the Andalusian Health Repository site are licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives License.