Myocardial protection: The adenosine story
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It has been recognized for many years that the purine nucleoside adenosine exerts numerous effects in mammalian myocardium. During the last decade, an in particular over the last 5 years, substantial evidence has accumulated that adenosine also exerts beneficial effects in the ischemic/reperfused myocardium. The cardioprotective effects of adenosine are manifest by attenuation of reversible postischemic ventricular dysfunction (i.e., stunning) and reduction of myocardial infarct size. These effects can be produced by augmenting endogenous adenosine levels with adenosine deaminase inhibitors and nucleoside transport inhibitors and by infusing adenosine (intracoronary or intravenous). Similar to adenosine's effects in nonischemic hearts, the cardioprotective effects of adenosine are mediated by activation of extracellular adenosine receptors. The results of studies with adenosine receptor agonists and antagonists indicate that adenosine's beneficial effect in reversibly and irreversibly injured myocardium is mediated primarily via adenosine A1 receptor activation. The protective effects of adenosine appear to occur during ischemia since adenosine infusion during reperfusion neither attenuates stunning nor reduces infarct size. Adenosine is cardioprotective in rats, rabbits, dogs, and pigs, and initial clinical reports indicate that adenosine may enhance myocardial protection during open heart surgery in humans. This review will summarize the current state of knowledge on the cardioprotective effects of adenosine in experimental and clinical studies. Drug Dev. Res. 39:314–318, 1996 © 1997 Wiley-Liss, Inc.Keywords:
Adenosine A3 receptor
Adenosine Deaminase Inhibitor
Adenosine A1 receptor
Purinergic Signalling
Myocardial Stunning
Cardioprotection
Adenosine kinase
Abstract Extracellular adenosine mediates diverse anti-inflammatory, angiogenic, and other signaling effects via binding to adenosine receptors, and it also regulates cell proliferation and death via activation of the intrinsic signaling pathways. Given the emerging role of adenosine and other purines in tumor growth and metastasis, this study evaluated the effects of adenosine on the invasion of metastatic prostate and breast cancer cells. Treatment with low micromolar concentrations of adenosine, but not other nucleosides or adenosine receptor agonists, inhibited subsequent cell invasion and migration through Matrigel- and laminin-coated inserts. These inhibitory effects occurred via intrinsic receptor-independent mechanisms, despite the abundant expression of A2B adenosine receptors (ADORA2B). Extracellular nucleotides and adenosine were shown to be rapidly metabolized on tumor cell surfaces via sequential ecto-5′-nucleotidase (CD73/NT5E) and adenosine deaminase reactions with subsequent cellular uptake of nucleoside metabolites and their intracellular interconversion into ADP/ATP. This was accompanied by concurrent inhibition of AMP-activated protein kinase and other signaling pathways. No differences in the proliferation rates, cytoskeleton assembly, expression of major adhesion molecules [integrin-1β (ITGB1), CD44, focal adhesion kinase], and secretion of matrix metalloproteinases were detected between the control and treated cells, thus excluding the contribution of these components of invasion cascade to the inhibitory effects of adenosine. These data provide a novel insight into the ability of adenosine to dampen immune responses and prevent tumor invasion via two different, adenosine receptor–dependent and –independent mechanisms. Implications: This study suggests that the combined targeting of adenosine receptors and modulation of intracellular purine levels can affect tumor growth and metastasis phenotypes. Mol Cancer Res; 12(12); 1863–74. ©2014 AACR.
Adenosine A2B receptor
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P2 receptor
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Adenosine kinase
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Abstract —The objective of this investigation was to determine whether the regulation of extracellular adenosine levels by smooth muscle cells (SMCs) from conduit arteries (aorta) and resistance microvessels (renal arterioles) is different in spontaneously hypertensive rats (SHR) versus normotensive Wistar-Kyoto (WKY) rats. Basal extracellular adenosine levels were decreased in cultured aortic and arteriolar SHR SMCs, and the increase in extracellular adenosine levels induced by stimulation of the cAMP-adenosine pathway was less in aortic and arteriolar SHR SMCs. Extracellular adenosine levels were lower in SHR SMCs, however, even when the cAMP-adenosine pathway was inhibited with 3-isobutyl-1-methylxanthine. Inhibition of adenosine kinase with iodotubercidin and inhibition of adenosine deaminase with erythro-9-(2-hydroxy-3-nonyl) adenine increased extracellular adenosine; however, only inhibition of adenosine deaminase equalized extracellular adenosine levels in SHR versus WKY SMCs. Membrane-disrupted SHR SMCs metabolized exogenous adenosine faster than WKY SMCs did, and this difference was abolished by inhibition of adenosine deaminase but not adenosine kinase. SHR SMCs demonstrated a greater proliferative response than WKY SMCs. This enhanced proliferative response was not blocked by adenosine per se or inhibition of adenosine kinase but was blocked by inhibition of adenosine deaminase and by 2-chloroadenosine (adenosine deaminase–resistant adenosine analogue). We conclude that dysregulation of extracellular adenosine levels exists in SHR SMCs, that this dysregulation is not due to a defect in the cAMP-adenosine pathway but rather to enhanced activity of adenosine deaminase, and that the dysregulation of extracellular adenosine mediates the enhanced proliferative response of SHR SMCs.
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CD73 (ecto-5'-nucleotidase) on human gingival fibroblasts plays a role in the regulation of intracellular cAMP levels through the generation of adenosine, which subsequently activates adenosine receptors. In this study, we examined the involvement of ecto-adenosine deaminase, which can be anchored to CD26 on human gingival fibroblasts, in metabolizing adenosine generated by CD73, and thus attenuating adenosine receptor activation. Ecto-adenosine deaminase expression on fibroblasts could be increased by pre-treatment with a lysate of Jurkat cells, a cell line rich in cytoplasmic adenosine deaminase. Interestingly, the cAMP response to adenosine generated from 5'-AMP via CD73 and the ability of 5'-AMP to induce hyaluronan synthase 1 mRNA were significantly decreased by the pre-treatment of fibroblasts with Jurkat cell lysate. This inhibitory effect was reversed by the specific adenosine deaminase inhibitor. These results suggest that ecto-adenosine deaminase metabolizes CD73-generated adenosine and regulates adenosine receptor activation.
Adenosine A2B receptor
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Adenosine, acting both through G-protein coupled adenosine receptors and intracellularly, plays a complex role in multiple physiological and pathophysiological processes by modulating neuronal plasticity, astrocytic activity, learning and memory, motor function, feeding, control of sleep and aging. Adenosine is involved in stroke, epilepsy and neurodegenerative pathologies. Extracellular concentration of adenosine in the brain is tightly regulated. Adenosine may be generated intracellularly in the central nervous system from degradation of AMP or from the hydrolysis of S-adenosyl homocysteine, and then exit via bi-directional nucleoside transporters, or extracellularly by the metabolism of released nucleotides. Inactivation of extracellular adenosine occurs by transport into neurons or neighboring cells, followed by either phosphorylation to AMP by adenosine kinase or deamination to inosine by adenosine deaminase. Modulation of the nucleoside transporters or of the enzymatic activities involved in the metabolism of adenosine, by affecting the levels of this nucleoside and the activity of adenosine receptors, could have a role in the onset or the development of central nervous system disorders, and can also be target of drugs for their treatment. In this review, we focus on the contribution of 5′-nucleotidases, adenosine kinase, adenosine deaminase, AMP deaminase, AMP-activated protein kinase and nucleoside transporters in epilepsy, cognition, and neurodegenerative diseases with a particular attention on amyotrophic lateral sclerosis and Huntington’s disease. We include several examples of the involvement of components of the adenosine metabolism in learning and of the possible use of modulators of enzymes involved in adenosine metabolism or nucleoside transporters in the amelioration of cognition deficits.
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1. A newly found action of adenosine in neurons, which may have an important physiological function in the growth and development of the sympathetic nervous system, is described. Adenosine (1‐100 microM) inhibited neurite outgrowth within the first 24 h and killed about 80% of sympathetic neurons supported by nerve growth factor over the next 2 days in culture. Neurons supported by excess KCl, forskolin or phorbol 12,13‐dibutyrate were equally susceptible to the toxic actions of adenosine. Inosine, guanosine or hypoxanthine (all 100‐300 microM) were without effect on neuronal growth and survival. 2. Specific agonists of adenosine A1 and A2 receptors were not neurotoxic, and toxic effects of adenosine were not antagonized by aminophylline. These results rule out involvement of adenosine receptors and the adenylyl cyclase‐cAMP signalling system in neurotoxic actions of adenosine. 3. Adenosine toxicity was prevented by inhibitors of the adenosine membrane transporter, suggesting an intracellular site of action of adenosine. 4. Inhibitors of adenosine deaminase dramatically facilitated the toxic action so that physiologically relevant concentrations of adenosine were neurotoxic. 5. Adenosine kinase activity of sympathetic neurons was dose‐dependently inhibited by 5'‐iodotubercidin (3‐100 nM). 5'‐Iodotubercidin (100 nM) completely protected neurons against toxicity of adenosine plus adenosine deaminase inhibitors. These results provide convincing evidence that phosphorylation of the nucleoside is an essential requirement for initiation of adenosine toxicity. 6. Sympathetic neurons were successfully rescued from the lethal effects of adenosine deaminase inhibitor plus adenosine by uridine or 2‐deoxycytidine, but not by nicotinamide or 2‐deoxyguanosine, suggesting that depletion of pyrimidine nucleotides by phosphorylated adenosine compounds and consequent inhibition of DNA synthesis produces neuronal death. 7. DNA fragmentation, assessed by the fluorescent dye bisbenzimide and by the TUNEL (terminal deoxynucleotidyl transferase‐mediated nick end labelling) method, indicated that neuronal death induced by adenosine was apoptotic. 8. We conclude that adenosine deaminase and adenosine kinase play an important role in the metabolism of intracellular concentrations of adenosine and thereby regulate the growth and development of sympathetic neurons. Our study highlights, for the first time, the importance of adenosine as a mediator of programmed cell death of neurons supported by nerve growth factor.
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Adenosine A2B receptor
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Objectives: Adenosine is an endogenous nucleoside that signals through G-protein coupled receptors. Extracellular adenosine is required for receptor activation and two pathways have been identified for formation and cellular release of adenosine. The CLASSICAL pathway relies on intracellular formation of adenosine from adenine nucleotides and cellular efflux of adenosine via equilibrative nucleoside transporters (ENTs). The ALTERNATE pathway involves cellular release of adenine nucleotides, hydrolysis via ecto-5'-nucleotidases and extracellular formation of adenosine. Methods: A rat model of cerebral ischemia and primary cultures of rat forebrain astrocytes and neurons were used. Results: Using a rat model of cerebral ischemia, the ENT1 inhibitor nitrobenzylmercaptopurine ribonucleoside (NBMPR) significantly increased post-ischemic forebrain adenosine levels and significantly decreased hippocampal neuron injury relative to saline-treatment. NBMPR-induced increases in adenosine receptor activation were not detected, suggesting that altering the intracellular:extracellular distribution of adenosine can affect ischemic outcome. Using primary cultures of rat forebrain astrocytes and neurons, adenosine release was evoked by ischemic-like conditions. Dipyridamole, an inhibitor of ENTs, was more effective at inhibiting adenosine release from neurons than from astrocytes. In contrast, α , β-methylene ADP, an inhibitor of ecto-5'-nucleotidase, was effective at inhibiting adenosine release from astrocytes, but not from neurons. Thus, during ischemic-like conditions, neurons released adenosine via the CLASSICAL pathway, while astrocytes released adenosine via the ALTERNATE pathway. Discussion: These cell type differences in pathways for adenosine formation during ischemia may allow transport inhibitors to block simultaneously adenosine release from neurons and adenosine uptake into astrocytes. In principle, this could improve neuronal ATP levels without decreasing adenosine receptor activation.
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