Short communication: ischemia/reperfusion tolerance is time-of-day-dependent: mediation by the cardiomyocyte circadian clock.
Short communication: ischemia/reperfusion tolerance is time-of-day-dependent: mediation by the cardiomyocyte circadian clock.
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DOI：
10.1161/circresaha.109.209346
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发表时间：
2010-02-19
影响因子：
20.1
通讯作者：
Young ME
中科院分区：
文献类型：
--
作者：
Durgan DJ;Pulinilkunnil T;Villegas-Montoya C;Garvey ME;Frangogiannis NG;Michael LH;Chow CW;Dyck JR;Young ME
心血管生理学和病理生理学在一天中变化很大。例如，心肌梗塞（MI）发作在人类的清晨期间发生率更高。然而，MI耐受性是否表现出时间依赖性尚不清楚。研究缺血性损伤的时间是否影响小鼠的临床相关结局。使用闭胸左前降支冠状动脉闭塞模型，在一天中的不同时间对野生型（WT）小鼠进行缺血/再灌注（I/R;缺血45分钟，然后再灌注一天或一个月）。再灌注一天后，在睡眠-觉醒过渡期（ZT 12）经受缺血的心脏导致梗死面积比在觉醒-睡眠过渡期（ZT 0）经受缺血的心脏增加3.5倍。再灌注一个月后，与ZT 0相比，ZT 12的既往缺血事件导致显著更大的梗死体积、纤维化和不良重塑，以及更大的收缩功能抑制。心肌细胞生物钟（称为CCM小鼠）的基因消融减弱/消除了WT心脏中观察到的I/R结果的时间变化。对WT和CCM心脏中Akt和GSK-3β的研究表明，这些激酶是心肌细胞生物钟和I/R耐受性之间的潜在机制联系。我们揭示了一个深刻的时间依赖性的I/R耐受，这是由心肌细胞的昼夜节律钟介导的。对I/R耐受节律的进一步了解将为缺血性心功能不全的病因学和治疗提供新的见解。
Cardiovascular physiology and pathophysiology vary dramatically over the course of the day. For example, myocardial infarction (MI) onset occurs with greater incidence during the early morning hours in humans. However, whether MI tolerance exhibits a time-of-day-dependence is unknown. To investigate whether time-of-day of an ischemic insult influences clinically-relevant outcomes in mice. Wild-type (WT) mice were subjected to ischemia/reperfusion (I/R; 45 minutes ischemia followed by one day or one month reperfusion) at distinct times of the day, using the closed-chest left anterior descending coronary artery occlusion model. Following one day of reperfusion, hearts subjected to ischemia at the sleep-to-wake transition (ZT12) resulted in 3.5-fold increases in infarct size compared to hearts subjected to ischemia at the wake-to-sleep transition (ZT0). Following one month of reperfusion, prior ischemic event at ZT12 versus ZT0 resulted in significantly greater infarct volume, fibrosis, and adverse remodeling, as well as greater depression of contractile function. Genetic ablation of the cardiomyocyte circadian clock (termed CCM mice) attenuated/abolished time-of-day variations in I/R outcomes observed in WT hearts. Investigation of Akt and GSK-3β in WT and CCM hearts identified these kinases as potential mechanistic ties between the cardiomyocyte circadian clock and I/R tolerance. We expose a profound time-of-day-dependence for I/R tolerance, which is mediated by the cardiomyocyte circadian clock. Further understanding of I/R tolerance rhythms will potentially provide novel insight regarding the etiology and treatment of ischemia-induced cardiac dysfunction.