title: Chronodisruption increases cardiovascular risk in zebrafish via reduced clearance of senescent erythrocytes.
abstract: 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.
authors.affiliation: Institute of Zoology, University Innsbruck , Innsbruck , Austria .
authors.forename: Margit
authors.initials: M
authors.lastname: Egg
authors.forename: Monika
authors.initials: M
authors.lastname: Paulitsch
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Ennemoser
authors.forename: Andrea
authors.initials: A
authors.lastname: Wüstenhagen
authors.forename: Thorsten
authors.initials: T
authors.lastname: Schwerte
authors.forename: Adolf Michael
authors.initials: AM
authors.lastname: Sandbichler
authors.forename: Birgit
authors.initials: B
authors.lastname: Fiechtner
authors.forename: Louise
authors.initials: L
authors.lastname: Köblitz
authors.forename: Caroline
authors.initials: C
authors.lastname: Prem
authors.forename: Bernd
authors.initials: B
authors.lastname: Pelster
mesh_terms: D000818:Animals; D017209:Apoptosis; D002318:Cardiovascular Diseases / Q000097:blood / Q000209:etiology* / Q000235:genetics / Q000503:physiopathology; D016922:Cellular Senescence / Q000528:radiation effects; D021081:Chronobiology Disorders / Q000097:blood / Q000150:complications* / Q000235:genetics / Q000503:physiopathology; D002940:Circadian Rhythm / Q000528:radiation effects; D004912:Erythrocytes / Q000378:metabolism / Q000473:pathology* / Q000528:radiation effects; D004921:Erythropoietin / Q000235:genetics / Q000378:metabolism; D000860:Hypoxia / Q000097:blood / Q000150:complications* / Q000235:genetics / Q000503:physiopathology; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism; D008027:Light; D017440:Photoperiod; D012307:Risk Factors; D013997:Time Factors; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism; D015027:Zebrafish / Q000097:blood* / Q000196:embryology / Q000235:genetics; D029961:Zebrafish Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D042461:Vascular Endothelial Growth Factor A; C583604:Vegfaa protein, zebrafish; D029961:Zebrafish Proteins; C523494:epoa protein, zebrafish; D004921:Erythropoietin
keywords: Cardiovascular diseases; chronodisruption; circadian rhythm; erythrocytes; hypoxia; hypoxia inducible factor