Young Martin E, Brewer Rachel A, Peliciari-Garcia Rodrigo A, Collins Helen E, He Lan, Birky Tana L, Peden Bradley W, Thompson Emily G, Ammons Billy-Joe, Bray Molly S, Chatham John C, Wende Adam R, Yang Qinglin, Chow Chi-Wing, Martino Tami A, Gamble Karen L
Division of Cardiovascular Diseases, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA
Division of Cardiovascular Diseases, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA.
J Biol Rhythms. 2014 Aug;29(4):257-76. doi: 10.1177/0748730414543141.
Circadian clocks are cell autonomous, transcriptionally based, molecular mechanisms that confer the selective advantage of anticipation, enabling cells/organs to respond to environmental factors in a temporally appropriate manner. Critical to circadian clock function are 2 transcription factors, CLOCK and BMAL1. The purpose of the present study was to reveal novel physiologic functions of BMAL1 in the heart, as well as to determine the pathologic consequences of chronic disruption of this circadian clock component. To address this goal, we generated cardiomyocyte-specific Bmal1 knockout (CBK) mice. Following validation of the CBK model, combined microarray and in silico analyses were performed, identifying 19 putative direct BMAL1 target genes, which included a number of metabolic (e.g., β-hydroxybutyrate dehydrogenase 1 [Bdh1]) and signaling (e.g., the p85α regulatory subunit of phosphatidylinositol 3-kinase [Pik3r1]) genes. Results from subsequent validation studies were consistent with regulation of Bdh1 and Pik3r1 by BMAL1, with predicted impairments in ketone body metabolism and signaling observed in CBK hearts. Furthermore, CBK hearts exhibited depressed glucose utilization, as well as a differential response to a physiologic metabolic stress (i.e., fasting). Consistent with BMAL1 influencing critical functions in the heart, echocardiographic, gravimetric, histologic, and molecular analyses revealed age-onset development of dilated cardiomyopathy in CBK mice, which was associated with a severe reduction in life span. Collectively, our studies reveal that BMAL1 influences metabolism, signaling, and contractile function of the heart.
昼夜节律钟是细胞自主的、基于转录的分子机制,赋予了预测的选择优势,使细胞/器官能够以时间上适当的方式对环境因素做出反应。昼夜节律钟功能的关键是两种转录因子,即CLOCK和BMAL1。本研究的目的是揭示BMAL1在心脏中的新生理功能,以及确定该昼夜节律钟组件长期破坏的病理后果。为了实现这一目标,我们构建了心肌细胞特异性Bmal1基因敲除(CBK)小鼠。在验证CBK模型后,进行了联合微阵列和计算机分析,鉴定出19个假定的直接BMAL1靶基因,其中包括一些代谢基因(如β-羟基丁酸脱氢酶1 [Bdh1])和信号传导基因(如磷脂酰肌醇3激酶的p85α调节亚基[Pik3r1])。后续验证研究的结果与BMAL1对Bdh1和Pik3r1的调控一致,在CBK心脏中观察到酮体代谢和信号传导的预测损伤。此外,CBK心脏表现出葡萄糖利用降低,以及对生理代谢应激(即禁食)的不同反应。与BMAL1影响心脏的关键功能一致,超声心动图、重量分析、组织学和分子分析显示CBK小鼠出现年龄相关性扩张型心肌病,这与寿命严重缩短有关。总的来说,我们的研究表明BMAL1影响心脏的代谢、信号传导和收缩功能。