2024-03-28T08:26:37Zhttp://repisalud.isciii.es/oai/requestoai:repisalud.isciii.es:20.500.12105/79522022-09-29T12:03:58Zcom_20.500.12105_2145com_20.500.12105_2051com_20.500.12105_2144col_20.500.12105_2146
Repisalud
author
Rivera-Torres, Jose
author
Calvo, Conrado J.
author
Llach, Anna
author
Guzman-Martinez, Gabriela
author
Caballero, Ricardo
author
Gonzalez-Gomez, Cristina
author
Jimenez-Borreguero, Luis J.
author
Guadix, Juan A
author
Osorio, Fernando G
author
López-Otín, Carlos
author
Herraiz-Martínez, Adela
author
Cabello, Nuria
author
Vallmitjana, Alex
author
Benítez, Raul
author
Gordon, Leslie B
author
Jalife, Jose
author
Pérez-Pomares, José M
author
Tamargo, Juan
author
Delpón, Eva
author
Hove-Madsen, Leif
author
Filgueiras-Rama, David
author
Andres, Vicente
funder
Ministerio de Economía y Competitividad (España)
funder
Unión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF)
funder
Instituto de Salud Carlos III
funder
Unión Europea
funder
Fundación Cajastur
funder
Fundación ProCNIC
2019-07-19T06:50:17Z
2019-07-19T06:50:17Z
2016
Proc Natl Acad Sci U S A. 2016; 113(46):E7250-E7259
0027-8424
http://hdl.handle.net/20.500.12105/7952
27799555
10.1073/pnas.1603754113
1091-6490
Proceedings of the National Academy of Sciences of the United States of America
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.
eng
Hutchinson–Gilford progeria syndrome
calcium handling
connexin43
prelamin A
progerin
Cardiac electrical defects in progeroid mice and Hutchinson-Gilford progeria syndrome patients with nuclear lamina alterations
journal article
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URL
https://repisalud.isciii.es/bitstream/20.500.12105/7952/1/CardiacElectricalDefectsProgeroid_2016.pdf
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CardiacElectricalDefectsProgeroid_2016.pdf.txt