RT Journal Article
T1 Cardiac electrical defects in progeroid mice and Hutchinson-Gilford progeria syndrome patients with nuclear lamina alterations.
A1 Rivera-Torres, Jose
A1 Calvo, Conrado J
A1 Llach, Anna
A1 Guzman-Martinez, Gabriela
A1 Caballero, Ricardo
A1 Gonzalez-Gomez, Cristina
A1 Jimenez-Borreguero, Luis J
A1 Guadix, Juan A
A1 Osorio, Fernando G
A1 Lopez-Otin, Carlos
A1 Herraiz-Martinez, Adela
A1 Cabello, Nuria
A1 Vallmitjana, Alex
A1 Benitez, Raul
A1 Gordon, Leslie B
A1 Jalife, Jose
A1 Perez-Pomares, Jose M
A1 Tamargo, Juan
A1 Delpón, Eva
A1 Hove-Madsen, Leif
A1 Filgueiras-Rama, David
A1 Andres, Vicente
K1 Hutchinson–Gilford progeria syndrome
K1 calcium handling
K1 connexin43
K1 prelamin A
K1 progerin
AB 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.
PB Oxford University Press
YR 2016
FD 2016-10-31
LK http://hdl.handle.net/10668/10568
UL http://hdl.handle.net/10668/10568
LA en
NO Rivera-Torres J, Calvo CJ, Llach A, Guzmán-Martínez G, Caballero R, González-Gómez C, et al. Cardiac electrical defects in progeroid mice and Hutchinson-Gilford progeria syndrome patients with nuclear lamina alterations. Proc Natl Acad Sci U S A. 2016 Nov 15;113(46):E7250-E7259
NO This work was supportedby Spanish Ministry of Economy and Competitiveness (MINECO) GrantsSAF2010-16044 and SAF2013-46663-R (to V.A.), SAF2011-30312 and SAF2014-58286-C2-1-R (to L.H.-M.), SAF2011-30088 (to E.D.), and SAF2014-52413-R (toC.L.-O.) and Fondo de Investigación Sanitaria del Instituto de Salud Carlos IIIGrants RD12/0042/0028 (to V.A.), RD12/0042/0011 (to J.T.), and RD12/0042/0002 (to L.H.-M.), with cofunding from the Fondo Europeo de DesarrolloRegional and the Progeria Research Foundation. J.A.G. is the recipient of aU-Mobility Grant from the Marie Curie cofunding of Regional, National andInternational Programme (Grant 246550). The Instituto Universitario de Onco-logía is supported by Obra Social Cajastur. The CNIC is supported by theMINECO and the Pro CNIC Foundation, and it is a Severo Ochoa Center ofExcellence (MINECO Award SEV-2015-0505).
DS RISalud
RD Apr 4, 2025