Physiopathology of the embryonic heart (with special emphasis on hypoxia and reoxygenation)

Raddatz, Eric; Gardier, Stéphany; Sarre, Alexandre

doi:10.1016/j.ancard.2006.02.007

Cited by 8 publications

(7 citation statements)

References 128 publications

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“…Although we cannot completely exclude artifacts from the dissection procedure, transient hypoxia or other factors (Raddatz et al, 2006), the most commonly observed arrhythmia was AV conduction block (5/62). In one E9.5 heart, we also observed conduction block at the IVG separating the LV and RV segments of the heart tube (Fig.…”

Section: Resultsmentioning

confidence: 99%

Atrioventricular conduction and arrhythmias at the initiation of beating in embryonic mouse hearts

Chen

Diego

Chang

et al. 2010

Developmental Dynamics

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To investigate cardiac physiology at the onset of heart beating in embryonic mouse hearts, we performed optical imaging of membrane potential (Vm) and/or intracellular calcium (Ca i ). Action potentials and Ca i transients were detected in~50% of mouse embryo hearts at E8.5, but in all hearts at E9.0, indicating that beating typically starts between E8-E9. Beating was eliminated by Ca channel blocker nifedipine and the I f blocker ZD7288, unaffected by tetrodotoxin and only mildly depressed by disabling sarcoplasmic (SR) and endoplasmic (ER) reticulum Ca cycling. From E8.5 to E10, conduction velocity increased from 0.2-1 mm/s to >5 mm/s in first ventricular and then atrial tissue, while remaining slow in other areas. Arrhythmias included atrioventricular reentry induced by adenosine. In summary, at the onset of beating, I f -dependent pacemaking drives both AP propagation and Ca i transient generation through activation of voltage-dependent Ca channels. Na channels and intracellular Ca cycling have minor roles. Developmental Dynamics 239:1941-1949,

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Section: Resultsmentioning

confidence: 99%

Atrioventricular conduction and arrhythmias at the initiation of beating in embryonic mouse hearts

Chen

Diego

Chang

et al. 2010

Developmental Dynamics

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“…Although the embryo and the fetus develop normally in a relatively hypoxic environment [7,31], cardiovascular function can be rapidly impaired by an accidental and transient intrauterine lack of oxygen [21] with possible long-term deleterious consequences. In the embryonic heart, the chrono-, dromo-and inotropic disturbances induced by anoxia-reoxygenation [39,48] are associated with overproduction of Reactive Oxygen Species (ROS) and significant alterations of signaling pathways. In particular, the region-specific activation of Mitogen-Activated Protein Kinases (MAPKs) [12,43] such as p38MAPK, extracellular signal-regulated kinase (ERK2) and c-jun N-terminal kinase (JNK) and stimulation of protein kinase C and nitric oxide synthases [44] are part of the mechanisms involved in the response to anoxia-reoxygenation, with slight differences relative to the ischemic-reperfused adult heart [18].…”

Section: Introductionmentioning

confidence: 99%

STAT3α interacts with nuclear GSK3beta and cytoplasmic RISK pathway and stabilizes rhythm in the anoxic-reoxygenated embryonic heart

Pedretti

Raddatz

2011

Basic Res Cardiol

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Activation of the Janus Kinase 2/Signal Transducer and Activator of Transcription 3 (JAK2/STAT3) pathway is known to play a key role in cardiogenesis and to afford cardioprotection against ischemia-reperfusion in adult. However, involvement of JAK2/STAT3 pathway and its interaction with other signaling pathways in developing heart transiently submitted to anoxia remains to be explored. Hearts isolated from 4-day-old chick embryos were submitted to anoxia (30 min) and reoxygenation (80 min) with or without the antioxidant MPG, the JAK2/STAT3 inhibitor AG490 or the PhosphoInositide-3-Kinase (PI3K)/Akt inhibitor LY-294002. Time course of phosphorylation of STAT3α(tyrosine705) and Reperfusion Injury Salvage Kinase (RISK) proteins [PI3K, Akt, Glycogen Synthase Kinase 3beta (GSK3beta), Extracellular signal-Regulated Kinase 2 (ERK2)] was determined in homogenate and in enriched nuclear and cytoplasmic fractions of the ventricle. STAT3 DNA-binding was determined. The chrono-, dromo- and inotropic disturbances were also investigated by electrocardiogram and mechanical recordings. Phosphorylation of STAT3α(tyr705) was increased by reoxygenation, reduced (~50%) by MPG or AG490 but not affected by LY-294002. STAT3 and GSK3beta were detected both in nuclear and cytoplasmic fractions while PI3K, Akt and ERK2 were restricted to cytoplasm. Reoxygenation led to nuclear accumulation of STAT3 but unexpectedly without DNA-binding. AG490 decreased the reoxygenation-induced phosphorylation of Akt and ERK2 and phosphorylation/inhibition of GSK3beta in the nucleus, exclusively. Inhibition of JAK2/STAT3 delayed recovery of atrial rate, worsened variability of cardiac cycle length and prolonged arrhythmias as compared to control hearts. Thus, besides its nuclear translocation without transcriptional activity, oxyradicals-activated STAT3α can rapidly interact with RISK proteins present in nucleus and cytoplasm, without dual interaction, and reduce the anoxia-reoxygenation-induced arrhythmias in the embryonic heart.

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“…Although the embryonic/fetal heart develops and functions normally in an intrauterine environment characterized by a low oxygen level, it reacts rapidly to abrupt oxygen shortage and reoxygenation (19,31,36,44). Such a stress was used in the context of ADO signaling to reveal possible functional differences between N and H6 hearts, which are not detectable otherwise.…”

Section: Adenosine Was Cardioprotective During Anoxiareoxygenationmentioning

confidence: 99%

A hypoxic episode during cardiogenesis downregulates the adenosinergic system and alters the myocardial anoxic tolerance

Robin

Marcillac

Raddatz

2015

American Journal of Physiology-Regulatory, Integrative and Comp

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Robin E, Marcillac F, Raddatz E. A hypoxic episode during cardiogenesis downregulates the adenosinergic system and alters the myocardial anoxic tolerance. Am J Physiol Regul Integr Comp Physiol 308: R614 -R626, 2015. First published January 28, 2015 doi:10.1152/ajpregu.00423.2014.-To what extent hypoxia alters the adenosine (ADO) system and impacts on cardiac function during embryogenesis is not known. Ectonucleoside triphosphate diphosphohydrolase (CD39), ecto-5=-nucleotidase (CD73), adenosine kinase (AdK), adenosine deaminase (ADA), equilibrative (ENT1,3,4), and concentrative (CNT3) transporters and ADO receptors A 1, A2A, A2B, and A3 constitute the adenosinergic system. During the first 4 days of development chick embryos were exposed in ovo to normoxia followed or not followed by 6 h hypoxia. ADO and glycogen content and mRNA expression of the genes were determined in the atria, ventricle, and outflow tract of the normoxic (N) and hypoxic (H) hearts. Electrocardiogram and ventricular shortening of the N and H hearts were recorded ex vivo throughout anoxia/reoxygenation Ϯ ADO. Under basal conditions, CD39, CD73, ADK, ADA, ENT1,3,4, CNT3, and ADO receptors were differentially expressed in the atria, ventricle, and outflow tract. In H hearts ADO level doubled, glycogen decreased, and mRNA expression of all the investigated genes was downregulated by hypoxia, except for A 2A and A3 receptors. The most rapid and marked downregulation was found for ADA in atria. H hearts were arrhythmic and more vulnerable to anoxia-reoxygenation than N hearts. Despite downregulation of the genes, exposure of isolated hearts to ADO 1) preserved glycogen through activation of A1 receptor and Akt-GSK3␤-GS pathway, 2) prolonged activity and improved conduction under anoxia, and 3) restored QT interval in H hearts. Thus hypoxia-induced downregulation of the adenosinergic system can be regarded as a coping response, limiting the detrimental accumulation of ADO without interfering with ADO signaling.anoxia-reoxygenation; arrhythmias; glycogen metabolism; hypoxia; adenosine signaling LOW OXYGEN LEVEL is a prerequisite for normal embryonic and fetal growth including the cardiovascular system. However, hypoxia-induced imbalance between O 2 supply and demand impacts gene expression, metabolism, growth, and function (13,17,20,21,33,45,48,50,53,56). Oxygen deprivation during critical periods of embryogenesis impairs heart development and function with hemodynamic disturbances resulting in fetal growth retardation and increasing the risk of cardiovascular disease in adulthood, the so-called "fetal programming" (8,12,26,38,47,57,59). Maternal hypoxemia, reduction in umbilical blood flow, or placental insufficiency can rapidly lead to acute or chronic ischemia and/or hypoxia, which exacerbates ATP-derived adenosine (ADO) production. Since ADO represents an important regulator of the embryonic cardiovascular function (35), the present study focuses on the modulation of the adenosinergic system by hypoxia and its functional consequences in the d...

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Physiopathology of the embryonic heart (with special emphasis on hypoxia and reoxygenation)

Cited by 8 publications

References 128 publications

Atrioventricular conduction and arrhythmias at the initiation of beating in embryonic mouse hearts

Atrioventricular conduction and arrhythmias at the initiation of beating in embryonic mouse hearts

STAT3α interacts with nuclear GSK3beta and cytoplasmic RISK pathway and stabilizes rhythm in the anoxic-reoxygenated embryonic heart

A hypoxic episode during cardiogenesis downregulates the adenosinergic system and alters the myocardial anoxic tolerance

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