期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2016
卷号：113
期号：46
页码：E7250-E7259
DOI：10.1073/pnas.1603754113
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：SignificanceDefective prelamin A processing causes cardiovascular alterations and premature death in Hutchinson-Gilford progeria syndrome (HGPS) patients and also occurs during physiological aging. We found overt repolarization abnormalities in HGPS patients at advanced disease stages. Similar alterations were present in progeroid Zmpste24-/- mice, which had cardiomyocytes that exhibited prolonged calcium transient duration and reduced sarcoplasmic reticulum calcium loading capacity and release, consistent with absence of isoproterenol-induced ventricular arrhythmias. Zmpste24-/- mice developed age-dependent bradycardia and PQ interval/QRS complex prolongation, likely contributing to premature death. These defects correlated with mislocalization of connexin43, which was also noted in heart tissue from HGPS patients. These results reveal molecular alterations that might cause cardiac rhythm alterations and premature death in HGPS. 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.
