Division of Cardiovascular Diseases, Department of Medicine, University of Alabama at Birmingham, 35294, USA.
Chronobiol Int. 2011 Apr;28(3):187-203. doi: 10.3109/07420528.2010.550406.
Circadian dyssynchrony of an organism (at the whole-body level) with its environment, either through light-dark (LD) cycle or genetic manipulation of clock genes, augments various cardiometabolic diseases. The cardiomyocyte circadian clock has recently been shown to influence multiple myocardial processes, ranging from transcriptional regulation and energy metabolism to contractile function. The authors, therefore, reasoned that chronic dyssychrony of the cardiomyocyte circadian clock with its environment would precipitate myocardial maladaptation to a circadian challenge (simulated shiftwork; SSW). To test this hypothesis, 2- and 20-month-old wild-type and CCM (Cardiomyocyte Clock Mutant; a model with genetic temporal suspension of the cardiomyocyte circadian clock at the active-to-sleep phase transition) mice were subjected to chronic (16-wks) biweekly 12-h phase shifts in the LD cycle (i.e., SSW). Assessment of adaptation/maladaptation at whole-body homeostatic, gravimetric, humoral, histological, transcriptional, and cardiac contractile function levels revealed essentially identical responses between wild-type and CCM littermates. However, CCM hearts exhibited increased biventricular weight, cardiomyocyte size, and molecular markers of hypertrophy (anf, mcip1), independent of aging and/or SSW. Similarly, a second genetic model of selective temporal suspension of the cardiomyocyte circadian clock (Cardiomyocyte-specific BMAL1 Knockout [CBK] mice) exhibits increased biventricular weight and mcip1 expression. Wild-type mice exhibit 5-fold greater cardiac hypertrophic growth (and 6-fold greater anf mRNA induction) when challenged with the hypertrophic agonist isoproterenol at the active-to-sleep phase transition, relative to isoproterenol administration at the sleep-to-active phase transition. This diurnal variation was absent in CCM mice. Collectively, these data suggest that the cardiomyocyte circadian clock likely influences responsiveness of the heart to hypertrophic stimuli.
机体（整体水平）与环境之间的昼夜节律失调，无论是通过光-暗（LD）周期还是时钟基因的遗传操作，都会增加各种心脏代谢疾病的风险。最近已经表明，心肌细胞的生物钟会影响多种心肌过程，从转录调控和能量代谢到收缩功能。因此，作者推断，心肌细胞生物钟与环境的慢性失同步会导致心肌对昼夜节律挑战（模拟轮班工作；SSW）的适应性降低。为了验证这一假说，对 2 个月和 20 个月大的野生型和 CCM（心肌细胞时钟突变体；一种在活跃到睡眠阶段转换时基因上暂停心肌细胞生物钟的模型）小鼠进行了慢性（16 周）每两周一次的 LD 周期 12 小时相位移动（即 SSW）。在整体稳态、体重、体液、组织学、转录和心脏收缩功能水平上评估适应性/不适应性，发现野生型和 CCM 同窝仔鼠的反应基本相同。然而，CCM 心脏表现出左右心室重量增加、心肌细胞增大和肥大的分子标志物（anf、mcip1）增加，这与衰老和/或 SSW 无关。同样，心肌细胞生物钟的另一种选择性时间暂停的遗传模型（心肌细胞特异性 BMAL1 敲除[CBK]小鼠）也表现出左右心室重量增加和 mcip1 表达增加。与睡眠到活跃阶段转换时给予异丙肾上腺素相比，在活跃到睡眠阶段转换时，野生型小鼠对肥大激动剂异丙肾上腺素的心脏肥大生长增加了 5 倍（anf mRNA 诱导增加了 6 倍）。这种昼夜变化在 CCM 小鼠中不存在。总的来说，这些数据表明，心肌细胞生物钟可能影响心脏对肥大刺激的反应性。
