Development of dilated cardiomyopathy in Bmal1-deficient mice
Development of dilated cardiomyopathy in Bmal1-deficient mice
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DOI：
10.1152/ajpheart.00238.2012
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发表时间：
2012-08-01
影响因子：
4.8
通讯作者：
Esser, Karyn A.
中科院分区：
文献类型：
--
作者：
Lefta, Mellani;Campbell, Kenneth S.;Esser, Karyn A.
莱夫塔·M，坎贝尔·KS，冯·H，金·J，埃塞尔·KA。 Bmal1 缺陷小鼠发生扩张型心肌病。 Am J Physiol Heart Circ Physiol 303：H475-H485，2012。首次发表于 2012 年 6 月 15 日； doi: 10.1152/ajpheart.00238.2012.-昼夜节律是生理和行为中大约 24 小时的振荡。在人类和动物模型中，昼夜节律紊乱与高血压、冠状动脉疾病、血脂异常和其他心血管疾病的发病率增加有关。缺乏核心生物钟基因、大脑和肌肉芳基碳氢化合物受体核易位蛋白 (Bmal1) 的小鼠会出现行为心律失常、过早死亡，并表现出多种器官病变。然而，关于 Bmal1 对心肌结构和功能完整性的作用尚缺乏数据。在本研究中，我们证明Bmal1(-/-)小鼠随着年龄的增长会出现扩张型心肌病，其特征是心肌壁变薄、左心室扩张和心脏功能下降。出生后不久，Bmal1(-/-) 小鼠的心肌重量短暂增加，随后消退，随后出现扩张和衰竭。离体工作心脏制剂显示，在扩张和衰竭开始时出现收缩性心室功能障碍，随后出现两种肌球蛋白重链亚型 mRNA 的下调。我们观察到肌节水平的结构紊乱，肌联蛋白异构体组成向更坚硬的 N2B 异构体转变。然而，单个心肌细胞中被动张力的产生并未增加。总的来说，这些发现表明，生物钟基因 Bmal1 的缺失会导致年龄相关的扩张型心肌病的发生，这与肌联蛋白亚型组成的变化、肌球蛋白重链基因表达的改变和肌节结构的破坏有关。
Lefta M, Campbell KS, Feng H, Jin J, Esser KA. Development of dilated cardiomyopathy in Bmal1-deficient mice. Am J Physiol Heart Circ Physiol 303: H475-H485, 2012. First published June 15, 2012; doi: 10.1152/ajpheart.00238.2012.-Circadian rhythms are approximate 24-h oscillations in physiology and behavior. Circadian rhythm disruption has been associated with increased incidence of hypertension, coronary artery disease, dyslipidemia, and other cardiovascular pathologies in both humans and animal models. Mice lacking the core circadian clock gene, brain and muscle aryl hydrocarbon receptor nuclear translocator (ARNT)-like protein (Bmal1), are behaviorally arrhythmic, die prematurely, and display a wide range of organ pathologies. However, data are lacking on the role of Bmal1 on the structural and functional integrity of cardiac muscle. In the present study, we demonstrate that Bmal1(-/-) mice develop dilated cardiomyopathy with age, characterized by thinning of the myocardial walls, dilation of the left ventricle, and decreased cardiac performance. Shortly after birth the Bmal1(-/-) mice exhibit a transient increase in myocardial weight, followed by regression and later onset of dilation and failure. Ex vivo working heart preparations revealed systolic ventricular dysfunction at the onset of dilation and failure, preceded by downregulation of both myosin heavy chain isoform mRNAs. We observed structural disorganization at the level of the sarcomere with a shift in titin isoform composition toward the stiffer N2B isoform. However, passive tension generation in single cardiomyocytes was not increased. Collectively, these findings suggest that the loss of the circadian clock gene, Bmal1, gives rise to the development of an age-associated dilated cardiomyopathy, which is associated with shifts in titin isoform composition, altered myosin heavy chain gene expression, and disruption of sarcomere structure.