Adenosine Receptors and Inflammation

Blackburn, Michael R.; Vance, Constance O.; Morschl, Éva; Wilson, Constance N.

doi:10.1007/978-3-540-89615-9_8

Cited by 149 publications

(151 citation statements)

References 299 publications

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“…This profile stems from a handful of changes spanning pathways (i.e. Gnb1, Nfat2c, Acta1, Prkar2b, Map3k2 and Pde3b), supporting effects of A 2A R activity on G protein and cAMP/PKA signalling downstream of the receptor [5,8,60]. Deletion of the A 2A R has been shown to reduce cAMP and PKA activation in other cell types [61], consistent with impacts of KO here ( Table 3).…”

Section: Discussionsupporting

confidence: 77%

Transcriptomic effects of adenosine 2A receptor deletion in healthy and endotoxemic murine myocardium

Ashton

Reichelt

Mustafa

et al. 2016

Purinergic Signalling

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Influences of adenosine 2A receptor (A 2A R) activity on the cardiac transcriptome and genesis of endotoxemic myocarditis are unclear. We applied transcriptomic profiling (39 K Affymetrix arrays) to identify A 2A R-sensitive molecules, revealed by receptor knockout (KO), in healthy and endotoxemic hearts. Baseline cardiac function was unaltered and only 37 A 2A R-sensitive genes modified by A 2A R KO (≥1.2-fold change, <5 % FDR); the five most induced are Mtr, Ppbp, Chac1, Ctsk and Cnpy2 and the five most repressed are Hp, Yipf4, Acta1, Cidec and Map3k2. Few canonical paths were impacted, with altered Gnb1, Prkar2b, Pde3b and Map3k2 (among others) implicating modified G protein/cAMP/PKA and cGMP/NOS signalling. Lipopolysaccharide (LPS; 20 mg/kg) challenge for 24 h modified >4100 transcripts in wild-type (WT) myocardium (≥1.5-fold change, FDR < 1 %); the most induced are Lcn2 (+590); Saa3 (+516); Serpina3n (+122); Cxcl9 (+101) and Cxcl1 (+89) and the most repressed are Car3 (−38); Adipoq (−17); Atgrl1/Aplnr (−14); H19 (−11) and Itga8 (−8). Canonical responses centred on inflammation, immunity, cell death and remodelling, with pronounced amplification of tolllike receptor (TLR) and underlying JAK-STAT, NFκB and MAPK pathways, and a 'cardio-depressant' profile encompassing suppressed ß-adrenergic, PKA and Ca 2+ signalling, electromechanical and mitochondrial function (and major shifts in transcripts impacting function/injury including Lcn2, S100a8/S100a9, Icam1/Vcam and Nox2 induction, and Adipoq, Igf1 and Aplnr repression). Endotoxemic responses were selectively modified by A 2A R KO, supporting inflammatory suppression via A 2A R sensitive shifts in regulators of NFκB and JAK-STAT signalling (IκBζ, IκBα, STAT1, CDKN1a and RRAS2) without impacting the cardio-depressant gene profile. Data indicate A 2A Rs exert minor effects in un-stressed myocardium and selectively suppress NFκB and JAK-STATsignalling and cardiac injury without influencing cardiac depression in endotoxemia.

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Section: Discussionsupporting

confidence: 77%

Transcriptomic effects of adenosine 2A receptor deletion in healthy and endotoxemic murine myocardium

Ashton

Reichelt

Mustafa

et al. 2016

Purinergic Signalling

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“…Future challenge will involve the definition of pharmacologic approaches, their translation from murine models toward the treatment of patients, and the identification of potentially unwanted side effects, such as alterations in coagulation or platelet function, 47,48 heart rate, and blood pressure, 49 or the consequences of chronic elevation of extracellular adenosine levels. 3,50 …”

Section: P2y 6 In Vascular Inflammation 2553mentioning

confidence: 99%

Selective induction of endothelial P2Y6 nucleotide receptor promotes vascular inflammation

Riegel

Faigle

Zug

et al. 2011

Blood

112

105

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During a systemic inflammatory response endothelial-expressed surface molecules have been strongly implicated in orchestrating immune responses. Previous studies have shown enhanced extracellular nucleotide release during acute inflammatory conditions. Therefore, we hypothesized that endothelial nucleotide receptors could play a role in vascular inflammation. To address this hypothesis, we performed screening experiments and exposed human microvascular endothelia to inflammatory stimuli, followed by measurements of P2Y or P2X transcriptional responses. These studies showed a selective induction of the P2Y 6 receptor (> 4-fold at 24 hours). Moreover, studies that used real-time reverse transcription-polymerase chain reaction, Western blot analysis, or immunofluorescence confirmed time-and dosedependent induction of P2Y 6 IntroductionVascular responses contribute significantly to inflammatory disorders such as systemic inflammatory response syndrome, sepsis, or acute lung injury. [1][2][3][4] Because of its large surface area and its anatomic position at the interface between the blood stream and surrounding tissues, the vascular endothelium has an exquisite regulatory function in orchestrating acute inflammatory responses. In fact, inflammatory cells such as phagocytes or lymphocytes can emigrate from the bloodstream in response to molecular changes on the surface of blood vessels that signal injury or infection. For example, ϳ 70 million polymorphonuclear neutrophils exit the vasculature per minute. These inflammatory cells move into underlying tissue by initially passing between endothelial cells that line the inner surface of blood vessels. This process, referred to as transendothelial migration is particularly prevalent in inflamed tissues. Although several studies suggested that specific molecules may establish "bottlenecks" to the control of the inflammatory response of the vasculature, only limited information exists about the biochemical events that initialize and dynamically regulate vascular inflammation.Under pathologic conditions such as acute inflammation, ischemia, or hypoxia extracellular nucleotides are released by multiple cell types. 5,6 For example, vascular endothelia, platelets, erythrocytes, or inflammatory cells can release nucleotides. Moreover, activation of extracellular nucleotide receptors (P2X receptors, ligand-gated ion channels; P2Y receptors, G protein-coupled receptors) has been implicated in driving an inflammatory phenotype in different disease models. 7 As such, studies in human and in mice implicate P2 receptor activation in pulmonary inflammation in the context of asthma 8 or chronic lung injury. 9 However, the role of nucleotide signaling during a systemic inflammatory response syndrome or sepsis remains largely unknown.On the basis of these findings, we hypothesized that vascular inflammation could drive transcriptional alterations of P2 receptors involved in the dynamic regulation of vascular inflammation. Consistent with this hypothesis, we found a selective induction of...

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“…For example, adenosine has been shown to inhibit neutrophil function and, in particular, neutrophil-mediated injury to endothelial cells. 12 It has been demonstrated in experimental models that exogenous or endogenous adenosine can inhibit neutrophil adhesion and injury to myocytes by an A2 receptor-mediated mechanism in cells activated with tumour necrosis factor-a. 13 The exact mechanisms of the cardioprotective effects of adenosine are not fully understood, although anti-inflammatory properties, inhibition of neutrophil and platelet activation and prevention of endothelial damage all seem to play principal roles.…”

Section: Pharmacological Prevention and Treatment Of Reperfusion Injumentioning

confidence: 99%

Pharmacological and physical prevention and treatment of no-reflow after primary percutaneous coronary intervention in ST-segment elevation myocardial infarction

Guo

Sheng²,

Xu³

et al. 2013

J Int Med Res

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After successful primary percutaneous coronary intervention in ST-segment elevation myocardial infarction, adequate myocardial reperfusion is not achieved in up to 50% of patients. This phenomenon of no-reflow is associated with a poor in-hospital and long-term prognosis. Four main factors are thought to contribute to the occurrence of no-reflow: ischaemic injury; reperfusion injury; distal embolization; susceptibility of the microcirculation to injury. This review evaluates the literature, and in particular the clinical trials, concerned with pharmacological and physical methods for prevention and treatment of no-reflow. A number of drugs may improve no-reflow experimentally and clinically, but some have not yet been associated with conclusive improvements in clinical outcome. The complex interacting factors in no-reflow make it unlikely that any single agent will be effective for all patients. Confirmed methods known to be beneficial in the prevention of no-reflow (such as aspirin therapy, chronic statin therapy, blood glucose control, thrombus aspiration in patients with a high thrombus burden and ischaemic preconditioning) should be offered to patients as often as possible, to prevent and treat no-reflow.

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Adenosine Receptors and Inflammation

Cited by 149 publications

References 299 publications

Transcriptomic effects of adenosine 2A receptor deletion in healthy and endotoxemic murine myocardium

Transcriptomic effects of adenosine 2A receptor deletion in healthy and endotoxemic murine myocardium

Selective induction of endothelial P2Y6 nucleotide receptor promotes vascular inflammation

Pharmacological and physical prevention and treatment of no-reflow after primary percutaneous coronary intervention in ST-segment elevation myocardial infarction

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