Cardiac electrical defects in progeroid mice and Hutchinson-Gilford progeria syndrome patients with nuclear lamina alterations
Por:
Rivera-Torres, J, Calvo, CJ, Llach, A, Guzman-Martinez, G, Caballero, R, Gonzalez-Gomez, C, Jimenez-Borreguero, LJ, Guadix, JA, Osorio, FG, Lopez-Otin, C, Herraiz-Martinezd, A, Cabello, N, Vallmitjana, A, Benitez, R, Gordon, LB, Jalife, J, Perez-Pomares, JM, Tamargo, J, Delpon, E, Hove-Madsen, L, Filgueiras-Rama, D, Andres, V
Publicada:
15 nov 2016
Resumen:
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 beta-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.
Filiaciones:
Rivera-Torres, J:
Ctr Nacl Invest Cardiovasc Carlos III CNIC, Madrid 28029, Spain
Calvo, CJ:
Ctr Nacl Invest Cardiovasc Carlos III CNIC, Madrid 28029, Spain
Univ Politecn Valencia, Informat & Commun Technol Inst ITACA, GEB, E-46022 Valencia, Spain
Univ Valencia, Fac Med & Odontol, Dept Physiol, Valencia 46010, Spain
Llach, A:
Hosp Santa Creu & Sant Pau, Inst Invest Biomed St Pau, Barcelona 08025, Spain
Guzman-Martinez, G:
Ctr Nacl Invest Cardiovasc Carlos III CNIC, Madrid 28029, Spain
Hosp Univ La Paz, Dept Cardiol, Cardiac Imaging Unit, Madrid 28046, Spain
Caballero, R:
Univ Complutense, Sch Med, Dept Pharmacol, E-28040 Madrid, Spain
Gonzalez-Gomez, C:
Ctr Nacl Invest Cardiovasc Carlos III CNIC, Madrid 28029, Spain
Jimenez-Borreguero, LJ:
Ctr Nacl Invest Cardiovasc Carlos III CNIC, Madrid 28029, Spain
Hosp La Princesa, Serv Cardiol, Madrid 28006, Spain
Guadix, JA:
Univ Malaga, Inst Invest Biomed Malaga IBIMA, Dept Anim Biol, E-29071 Malaga, Spain
Univ Malaga, Junta Andalucia, Ctr Andaluz Nanomed Biotecnol BIONAND, Campanillas 29590, Spain
Osorio, FG:
Univ Oviedo, Inst Univ Oncol, Dept Bioquim & Biol Mol, E-33006 Oviedo, Spain
Lopez-Otin, C:
Univ Oviedo, Inst Univ Oncol, Dept Bioquim & Biol Mol, E-33006 Oviedo, Spain
Herraiz-Martinezd, A:
Hosp Santa Creu & Sant Pau, Inst Invest Biomed St Pau, Barcelona 08025, Spain
Hosp Santa Creu & Sant Pau, Cardiovasc Res Ctr, Barcelona 08025, Spain
Cabello, N:
Hosp Santa Creu & Sant Pau, Inst Invest Biomed St Pau, Barcelona 08025, Spain
Hosp Santa Creu & Sant Pau, Cardiovasc Res Ctr, Barcelona 08025, Spain
Vallmitjana, A:
Univ Politecn Cataluna, Automat Control Dept, ES-08034 Barcelona, Spain
Benitez, R:
Univ Politecn Cataluna, Automat Control Dept, ES-08034 Barcelona, Spain
Gordon, LB:
Brown Univ, Alpert Med Sch, Dept Pediat, Providence, RI 02903 USA
Hasbro Childrens Hosp, Dept Pediat, Providence, RI 02903 USA
Boston Childrens Hosp, Div Crit Care Med, Dept Anesthesia, Boston, MA 02115 USA
Harvard Med Sch, Boston, MA 02115 USA
Jalife, J:
Ctr Nacl Invest Cardiovasc Carlos III CNIC, Madrid 28029, Spain
Univ Michigan, Dept Internal Med, Ann Arbor, MI 48109 USA
Univ Michigan, Ctr Arrhythmia Res, Ann Arbor, MI 48109 USA
Perez-Pomares, JM:
Univ Malaga, Inst Invest Biomed Malaga IBIMA, Dept Anim Biol, E-29071 Malaga, Spain
Tamargo, J:
Univ Complutense, Sch Med, Dept Pharmacol, E-28040 Madrid, Spain
Delpon, E:
Univ Complutense, Sch Med, Dept Pharmacol, E-28040 Madrid, Spain
Hove-Madsen, L:
Hosp Santa Creu & Sant Pau, Inst Invest Biomed St Pau, Barcelona 08025, Spain
Hosp Santa Creu & Sant Pau, Cardiovasc Res Ctr, Barcelona 08025, Spain
Filgueiras-Rama, D:
Ctr Nacl Invest Cardiovasc Carlos III CNIC, Madrid 28029, Spain
Hosp Clin San Carlos, Cardiac Electrophysiol Unit, Dept Cardiol, Madrid 28040, Spain
Andres, V:
Ctr Nacl Invest Cardiovasc Carlos III CNIC, Madrid 28029, Spain
Green Published, Bronze
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