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Cardiac electrical defects in progeroid mice and Hutchinson-Gilford progeria syndrome patients with nuclear lamina alterations.

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Date

2016-10-31

Authors

Rivera-Torres, Jose
Calvo, Conrado J
Llach, Anna
Guzman-Martinez, Gabriela
Caballero, Ricardo
Gonzalez-Gomez, Cristina
Jimenez-Borreguero, Luis J
Guadix, Juan A
Osorio, Fernando G
Lopez-Otin, Carlos

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Oxford University Press
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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.

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MeSH Terms

Adolescent
Adult
Animals
Arrhythmias, Cardiac
Calcium
Cardiac Conduction System Disease
Child
Child, Preschool
Connexin 43
Female
Heart
Humans
Male
Membrane Proteins
Metalloendopeptidases
Mice, Inbred C57BL
Mice, Knockout
Myocardium
Nuclear Lamina
Progeria
Sarcoplasmic Reticulum
Young Adult

DeCS Terms

Arritmias cardíacas
Calcio
Conexina 43
Lámina nuclear
Metaloendopeptidasas
Miocardio
Progeria

CIE Terms

Keywords

Hutchinson–Gilford progeria syndrome, calcium handling, connexin43, prelamin A, progerin

Citation

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