Egg Margit, Paulitsch Monika, Ennemoser Yvonne, Wüstenhagen Andrea, Schwerte Thorsten, Sandbichler Adolf Michael, Fiechtner Birgit, Köblitz Louise, Prem Caroline, Pelster Bernd
Institute of Zoology, University Innsbruck , Innsbruck , Austria .
Chronobiol Int. 2014 Jun;31(5):680-9. doi: 10.3109/07420528.2014.889703. Epub 2014 Feb 25.
The circadian clock and the hypoxic signaling pathway play critical roles in physiological homeostasis as well as in pathogenesis. The bi-directionality of the interaction between both pathways has been shown on physiological and only recently also on molecular level. But the consequences of a disturbed circadian rhythm for the hypoxic response and the cardiovascular system have never been addressed in any organism. Here we show that the hypoxic response of animals subjected to chronodisruption is reduced by approximately 30%, as reflected by decreased expression levels of hypoxia inducible factor 1 and its down-stream target genes erythropoietin, responsible for the generation of red blood cells (RBC) and vascular endothelial growth factor, which is essential for proper vascularization. Beside malformations of their vascular beds, chronodisrupted animals surprisingly revealed elevated numbers of senescent erythrocytes under normoxic conditions, due to a reduced clearance rate via apoptosis. Over-aged erythrocytes in turn are characterized by decreased oxygen transport capacities and an increased tendency for aggregation, explaining the higher mortality of chronodisrupted animals observed in our study. The present study shows for the first time that chronodisruption strongly interferes with the hypoxic signalling cascade, increasing the cardiovascular risk in zebrafish due to elevated proportions of senescent erythrocytes. The results might shed new light on the etiology of the increased cardiovascular risk observed among shiftworkers.
昼夜节律钟和缺氧信号通路在生理稳态以及发病机制中发挥着关键作用。这两条通路之间相互作用的双向性已在生理水平上得到证实，并且直到最近才在分子水平上得到证实。但是，昼夜节律紊乱对缺氧反应和心血管系统的影响在任何生物体中都从未得到过研究。在这里，我们表明，受到昼夜节律紊乱影响的动物的缺氧反应降低了约30%，这反映在缺氧诱导因子1及其下游靶基因促红细胞生成素（负责红细胞生成）和血管内皮生长因子（对正常血管形成至关重要）的表达水平降低上。除了血管床畸形外，受到昼夜节律紊乱影响的动物在常氧条件下令人惊讶地显示衰老红细胞数量增加，这是由于通过凋亡清除率降低所致。衰老的红细胞反过来又具有氧运输能力降低和聚集倾向增加的特征，这解释了我们研究中观察到的受到昼夜节律紊乱影响的动物死亡率较高的原因。本研究首次表明，昼夜节律紊乱强烈干扰缺氧信号级联反应，由于衰老红细胞比例升高，增加了斑马鱼的心血管风险。这些结果可能为轮班工作者中观察到的心血管风险增加的病因提供新的线索。
