The day/night proteome in the murine heart.
The day/night proteome in the murine heart.
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DOI：
10.1152/ajpregu.00011.2014
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发表时间：
2014-07
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通讯作者：
Peter S. Podobed;W. Pyle;S. Ackloo;Faisal J Alibhai;Elena V. Tsimakouridze;William F. Ratcliffe;A. Mackay;J. Simpson;D. Wright;G. Kirby;M. Young;T. Martino
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作者：
Peter S. Podobed;W. Pyle;S. Ackloo;Faisal J Alibhai;Elena V. Tsimakouridze;William F. Ratcliffe;A. Mackay;J. Simpson;D. Wright;G. Kirby;M. Young;T. Martino
昼夜节律对心血管健康和疾病是必不可少的。心脏结构和功能的时间协调主要集中在生理和基因表达水平，但这些分析总是不完整的，尤其是因为蛋白质是许多生物过程的基础。本研究旨在揭示心脏蛋白质组的昼夜变化及其对心脏功能的重要贡献。采用双向差示凝胶电泳法(2D-DGE)和液-质联用技术对24小时昼夜节律的小鼠心肌蛋白质组进行分析。日变化很大，因为∼7.8%(90/1,147)的斑点在24小时明(L)暗(D)周期的配对时间显示出统计变化。用JTK_Cycle研究相应基因表达的昼夜节律。我们接下来揭示，相对于L：D周期，在朗宁多夫灌流的心脏中，阻断L：D周期改变了蛋白质谱和心功能的昼夜变化。为了研究生物钟机制的作用，我们使用了心肌细胞时钟突变(CCM)小鼠。CCM肌丝表现出一天中时间依赖性的最大钙依赖性ATP消耗的丧失，并改变了磷酸化节律。此外，CCM心脏的蛋白质组显著改变，尤其是调节重要代谢途径的酶。最后，我们使用压力超负荷心肌肥厚模型来展示心脏疾病过程中的时间蛋白质组。我们的研究表明，一天中的时间对心脏蛋白质的丰度起着直接的作用，并表明了昼夜生物学对心血管结构和功能的一种新的机制贡献。
Circadian rhythms are essential to cardiovascular health and disease. Temporal coordination of cardiac structure and function has focused primarily at the physiological and gene expression levels, but these analyses are invariably incomplete, not the least because proteins underlie many biological processes. The purpose of this study was to reveal the diurnal cardiac proteome and important contributions to cardiac function. The 24-h day-night murine cardiac proteome was assessed by two-dimensional difference in gel electrophoresis (2D-DIGE) and liquid chromatography-mass spectrometry. Daily variation was considerable, as ∼7.8% (90/1,147) of spots exhibited statistical changes at paired times across the 24-h light- (L) dark (D) cycle. JTK_CYCLE was used to investigate underlying diurnal rhythms in corresponding mRNA. We next revealed that disruption of the L:D cycle altered protein profiles and diurnal variation in cardiac function in Langendorff-perfused hearts, relative to the L:D cycle. To investigate the role of the circadian clock mechanism, we used cardiomyocyte clock mutant (CCM) mice. CCM myofilaments exhibited a loss of time-of-day-dependent maximal calcium-dependent ATP consumption, and altered phosphorylation rhythms. Moreover, the cardiac proteome was significantly altered in CCM hearts, especially enzymes regulating vital metabolic pathways. Lastly, we used a model of pressure overload cardiac hypertrophy to demonstrate the temporal proteome during heart disease. Our studies demonstrate that time of day plays a direct role in cardiac protein abundance and indicate a novel mechanistic contribution of circadian biology to cardiovascular structure and function.