Involvement of CD73, equilibrative nucleoside transporters and inosine in rhythm and conduction disturbances mediated by adenosine A1 and A2A receptors in the developing heart

Robin, Eric; Sabourin, Jessica; Marcillac, Fabrice; Raddatz, Eric

doi:10.1016/j.yjmcc.2013.06.008

Cited by 9 publications

(15 citation statements)

References 89 publications

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“…The quantitative real-time PCR (qRT-PCR) has been performed as described in detail in our recent work (41). The following sets of oligonucleotides were purchased from Microsynth (Balgach, Switzerland): GAPDH, A 1AR, A2AAR, A2BAR, A3AR, AdK, CD39, CD73, ADA, ENT1, ENT3, ENT4, CNT3, and HIF-1␣ (Table 1).…”

Section: Quantitative Real-time Pcr Analysismentioning

confidence: 99%

“…The following sets of oligonucleotides were purchased from Microsynth (Balgach, Switzerland): GAPDH, A 1AR, A2AAR, A2BAR, A3AR, AdK, CD39, CD73, ADA, ENT1, ENT3, ENT4, CNT3, and HIF-1␣ (Table 1). The level of mRNA expression in A, V, and OT was investigated with GAPDH as a reference gene (41). The framework of the components of the adenosinergic system investigated in this study is represented in Fig.…”

Section: Quantitative Real-time Pcr Analysismentioning

confidence: 99%

“…Briefly, samples were denatured, separated on SDS-polyacrylamide gels, and electroblotted on nitrocellulose membranes (41). Membranes were blocked and probed overnight with phosphorylated or total form antibodies.…”

Section: Western Blottingmentioning

confidence: 99%

“…CD39 and CD73 sequentially convert ATP to ADO and ADA mediates conversion of ADO to inosine (INO). ADO is transported across cell membrane by equilibrative (ENT1, 3,4) or concentrative (CNT3) transporters and interacts with the four subtypes of ADO receptors (AR), i.e., A 1 AR, A 2A AR, A 2B AR, and A 3 AR (5,22,40,41,51). Pharmacological disturbances of nucleosides metabolism and transport in the embryonic heart can rapidly lead to interstitial accumulation of ADO and INO and provoke arrhythmias in an autocrine/paracrine manner through A 1 AR and A 2A AR stimulation and ERK2 activation (41).…”

mentioning

confidence: 99%

“…ADO is transported across cell membrane by equilibrative (ENT1, 3,4) or concentrative (CNT3) transporters and interacts with the four subtypes of ADO receptors (AR), i.e., A 1 AR, A 2A AR, A 2B AR, and A 3 AR (5,22,40,41,51). Pharmacological disturbances of nucleosides metabolism and transport in the embryonic heart can rapidly lead to interstitial accumulation of ADO and INO and provoke arrhythmias in an autocrine/paracrine manner through A 1 AR and A 2A AR stimulation and ERK2 activation (41). Activation of ADO receptors is also known to play a major role in protection of heart development against exposure to intrauterine hypoxia (39,58); in regulation of heart rate, conduction, and contractility; and in modulation of substrate metabolism, in particular glucose uptake and utilization (18).…”

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confidence: 99%

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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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Section: Quantitative Real-time Pcr Analysismentioning

confidence: 99%

Section: Quantitative Real-time Pcr Analysismentioning

confidence: 99%

Section: Western Blottingmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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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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CD73-TNAP crosstalk regulates the hypertrophic response and cardiomyocyte calcification due to α1 adrenoceptor activation

et al. 2014

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Cluster of differentiation 73 (CD73) is an ecto-5' nucleotidase which catalyzes the conversion of AMP to adenosine. One of the many functions of adenosine is to suppress the activity of tissue nonspecific alkaline phosphatase (TNAP), an enzyme important in regulating intracellular calcification. Since myocardial calcification is associated with various cardiac disease states, we studied the individual roles and crosstalk between CD73 and TNAP in regulating myocyte responses to the α1 adrenoceptor agonist phenylephrine in terms of calcification and hypertrophy. Cultured neonatal rat cardiomyocytes were treated with 10 µM phenylephrine for 24 h in the absence or presence of the stable adenosine analog 2-chloro-adenosine, the TNAP inhibitor tetramisole or the CD73 inhibitor α,β-methylene ADP. Phenylephrine produced marked hypertrophy as evidenced by significant increases in myocyte surface area and ANP gene expression, as well as calcification determined by Alizarin Red S staining. These responses were associated with reduced CD73 gene and protein expression and CD73 activity. Conversely, TNAP expression and activity were significantly increased although both were suppressed by 2-chloro-adenosine. CD73 inhibition alone significantly reduced myocyte-derived adenosine levels by >50 %, and directly induced hypertrophy and calcification in the absence of phenylephrine. These responses and those to phenylephrine were abrogated by TNAP inhibition. We conclude that TNAP contributes to the hypertrophic effect of phenylephrine, as well as its ability to produce cardiomyocyte calcification. These responses are minimized by CD73-dependent endogenously produced adenosine.

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Comparative genomic and expression analysis of the adenosine signaling pathway members in Xenopus

Tocco

Pinson²,

Thiébaud

et al. 2014

Purinergic Signalling

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Adenosine is an endogenous molecule that regulates many physiological processes via the activation of four specific G-protein-coupled ADORA receptors. Extracellular adenosine may originate either from the hydrolysis of released ATP by the ectonucleotidases or from cellular exit via the equilibrative nucleoside transporters (SLC29A). Adenosine extracellular concentration is also regulated by its successive hydrolysis into uric acid by membrane-bound enzymes or by cell influx via the concentrative nucleoside transporters (SLC28A). All of these members constitute the adenosine signaling pathway and regulate adenosine functions. Although the roles of this pathway are quite well understood in adults, little is known regarding its functions during vertebrate embryogenesis. We have used Xenopus laevis as a model system to provide a comparative expression map of the different members of this pathway during vertebrate development. We report the characterization of the different enzymes, receptors, and nucleoside transporters in both X. laevis and X. tropicalis, and we demonstrate by phylogenetic analyses the high level of conservation of these members between amphibians and mammals. A thorough expression analysis of these members during development and in the adult frog reveals that each member displays distinct specific expression patterns. These data suggest potentially different developmental roles for these proteins and therefore for extracellular adenosine. In addition, we show that adenosine levels during amphibian embryogenesis are very low, confirming that they must be tightly controlled for normal development.

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Involvement of CD73, equilibrative nucleoside transporters and inosine in rhythm and conduction disturbances mediated by adenosine A1 and A2A receptors in the developing heart

Cited by 9 publications

References 89 publications

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

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

CD73-TNAP crosstalk regulates the hypertrophic response and cardiomyocyte calcification due to α1 adrenoceptor activation

Comparative genomic and expression analysis of the adenosine signaling pathway members in Xenopus

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