The Hypoxia-Adenosine Link during Myocardial Ischemia—Reperfusion Injury

Ruan, Wei; Ma, Xinxin; Bang, In Hyuk; Liang, Yafen; Muehlschlegel, Jochen D.; Tsai, Kuang‐Lei; Mills, Tingting; Yuan, Xiaoyi; Eltzschig, Holger K.

doi:10.3390/biomedicines10081939

Cited by 21 publications

(11 citation statements)

References 201 publications

(256 reference statements)

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“…Our results from oxygen experiments exclude a major regulatory role of oxygen on placental CD39. This is in contrast with previous studies demonstrating that mRNA- and protein levels, as well as the enzymatic function of CD39 are increased during ischemia, inflammation, or hypoxia ( Köhler et al, 2007 ; Ruan et al, 2022 ). For example, studies in a model of murine myocardial ischemia/reperfusion show a time-dependent induction of cardiac CD39 mRNA under the control of SP1 ( Eltzschig et al, 2009 ).…”

Section: Discussioncontrasting

confidence: 99%

CD39 abrogates platelet-derived factors induced IL-1β expression in the human placenta

Forstner

Guettler

Brugger

et al. 2023

Front. Cell Dev. Biol.

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Tissue insults in response to inflammation, hypoxia and ischemia are accompanied by the release of ATP into the extracellular space. There, ATP modulates several pathological processes, including chemotaxis, inflammasome induction and platelet activation. ATP hydrolysis is significantly enhanced in human pregnancy, suggesting that increased conversion of extracellular ATP is an important anti-inflammatory process in preventing exaggerated inflammation, platelet activation and hemostasis in gestation. Extracellular ATP is converted into AMP, and subsequently into adenosine by the two major nucleotide-metabolizing enzymes CD39 and CD73. Here, we aimed to elucidate developmental changes of placental CD39 and CD73 over gestation, compared their expression in placental tissue from patients with preeclampsia and healthy controls, and analyzed their regulation in response to platelet-derived factors and different oxygen conditions in placental explants as well as the trophoblast cell line BeWo. Linear regression analysis showed a significant increase in placental CD39 expression, while at the same time CD73 levels declined at term of pregnancy. Neither maternal smoking during first trimester, fetal sex, maternal age, nor maternal BMI revealed any effects on placental CD39 and CD73 expression. Immunohistochemistry detected both, CD39 and CD73, predominantly in the syncytiotrophoblast layer. Placental CD39 and CD73 expression were significantly increased in pregnancies complicated with preeclampsia, when compared to controls. Cultivation of placental explants under different oxygen conditions had no effect on the ectonucleotidases, whereas presence of platelet releasate from pregnant women led to deregulated CD39 expression. Overexpression of recombinant human CD39 in BeWo cells decreased extracellular ATP levels after culture in presence of platelet-derived factors. Moreover, platelet-derived factors-induced upregulation of the pro-inflammatory cytokine, interleukin-1β, was abolished by CD39 overexpression. Our study shows that placental CD39 is upregulated in preeclampsia, suggesting an increasing demand for extracellular ATP hydrolysis at the utero-placental interface. Increased placental CD39 in response to platelet-derived factors may lead to enhanced conversion of extracellular ATP levels, which in turn could represent an important anti-coagulant defense mechanism of the placenta.

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Section: Discussioncontrasting

confidence: 99%

CD39 abrogates platelet-derived factors induced IL-1β expression in the human placenta

Forstner

Guettler

Brugger

et al. 2023

Front. Cell Dev. Biol.

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“…Inhibition of this enzyme was recently reported to reduce infarct size, improve cardiac function, and prevent cell apoptosis and necroptosis in a mouse model of MI ( 56 ). Strategies to target the hypoxia-adenosine link that could be considered for a clinical trial were recently competently reviewed ( 57 ). Second, pharmacological blockade of the A2bR should reduce IL-6 production, which in turn is expected to be beneficial for cardiac healing.…”

Section: Discussionmentioning

confidence: 99%

IL-6 in the infarcted heart is preferentially formed by fibroblasts and modulated by purinergic signaling

Alter¹,

Henseler²,

Owenier³

et al. 2023

Journal of Clinical Investigation

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Plasma IL-6 is elevated after myocardial infarction (MI) and is associated with increased morbidity and mortality. Which cardiac cell type preferentially contributes to IL-6 and how its production is regulated is largely unknown. Here, we studied the cellular source and purinergic regulation of IL-6 formation in a murine MI model. IL-6, measured in various cell types in post MI hearts by qPCR, RNAscope and at protein level, was preferentially formed by fibroblasts (CFs). scRNAseq in infarcted mouse and human hearts confirmed this finding. Adenosine stimulated fibroblast IL-6 formation via A2bR in a Gq-dependent manner. CFs highly expressed Adora2b, rapidly degraded extracellular ATP to AMP but lacked CD73. In mice and humans Adora2B was also mainly expressed by fibroblasts (scRNAseq). Global IL-6 formation was assessed in isolated hearts in mice lacking CD73 on T-cells (CD4CD73 -/-) a condition known to be associated with adverse cardiac remodeling. The ischemia-induced release of IL-6 was strongly attenuated in CD4CD73 -/mice, suggesting adenosine-mediated modulation.Together this demonstrates that post-MI IL-6 is mainly derived from activated CFs and is controlled by T-cell derived adenosine. Purinergic metabolic cooperation between CFs and Tcells is a novel mechanism with therapeutic potential which modulates IL6 formation by the heart.

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“…Adenosine has been extensively studied as a mediator of cardiac protection during ischemia-reperfusion [ 106 ]. Adenosine is also involved in adaptive preconditioning responses that induce prolonged shifts in stress resistance and limit later remodeling changes and heart failure progression.…”

Section: Ars In Cardiovascular and Metabolic Diseasesmentioning

confidence: 99%

Pharmacology of Adenosine Receptors: Recent Advancements

Vincenzi,

Pasquini,

Contri

et al. 2023

Biomolecules

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Adenosine receptors (ARs) are widely acknowledged pharmacological targets yet are still underutilized in clinical practice. Their ubiquitous distribution in almost all cells and tissues of the body makes them, on the one hand, excellent candidates for numerous diseases, and on the other hand, intrinsically challenging to exploit selectively and in a site-specific manner. This review endeavors to comprehensively depict the substantial advancements witnessed in recent years concerning the development of drugs that modulate ARs. Through preclinical and clinical research, it has become evident that the modulation of ARs holds promise for the treatment of numerous diseases, including central nervous system disorders, cardiovascular and metabolic conditions, inflammatory and autoimmune diseases, and cancer. The latest studies discussed herein shed light on novel mechanisms through which ARs exert control over pathophysiological states. They also introduce new ligands and innovative strategies for receptor activation, presenting compelling evidence of efficacy along with the implicated signaling pathways. Collectively, these emerging insights underscore a promising trajectory toward harnessing the therapeutic potential of these multifaceted targets.

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The Hypoxia-Adenosine Link during Myocardial Ischemia—Reperfusion Injury

Cited by 21 publications

References 201 publications

CD39 abrogates platelet-derived factors induced IL-1β expression in the human placenta

CD39 abrogates platelet-derived factors induced IL-1β expression in the human placenta

IL-6 in the infarcted heart is preferentially formed by fibroblasts and modulated by purinergic signaling

Pharmacology of Adenosine Receptors: Recent Advancements

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