Physiological Roles of Vascular Nucleoside Transporters

Löffler, Michaela; Morote-García, Julio C.; Eltzschig, Shelley A.; Coe, Imogen R.; Eltzschig, Holger K.

doi:10.1161/atvbaha.106.126714

Cited by 147 publications

(134 citation statements)

References 115 publications

(171 reference statements)

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“…A recent study has described that during inflammation and hypoxia, there is a transcriptional increase in functional surface apyrase (CD39) and nucleotidase (CD73). In addition, following adenosine generation and receptor activation, adenosine diffuses away from the receptor and is rapidly transported from the extracellular toward the intracellular space mainly via equilibrative nucleoside transporters (ENT-1 and ENT-2) [40]. Having reached the intracellular space, adenosine can either undergo deamination by adenosine deaminase to inosine or conversion to AMP by adenosine kinase (AK) [37].…”

Section: Discussionmentioning

confidence: 99%

“…Having reached the intracellular space, adenosine can either undergo deamination by adenosine deaminase to inosine or conversion to AMP by adenosine kinase (AK) [37]. Current studies showed that time-dependent exposure of tissue to inflammation and hypoxia change adenosine metabolism, and this change is related to hypoxia-inducible factor (HIF)-1α transcriptional repression of ENT-2 and AK, resulting in decreased capacity to transport extracellular adenosine and intracellular adenosine accumulation, increasing adenosine levels and its signaling, with additional protecting effects to vascular endothelia and tissue [39,40].…”

Section: Discussionmentioning

confidence: 99%

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Anti-inflammatory effects of purine nucleosides, adenosine and inosine, in a mouse model of pleurisy: evidence for the role of adenosine A2 receptors

Lapa

Silva

Cabrini

et al. 2012

Purinergic Signalling

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Adenosine and its metabolite, inosine, have been described as molecules that participate in regulation of inflammatory response. The aim of this study was to investigate the effect of adenosine and inosine in a mouse model of carrageenan-induced pleurisy as well as the participation of adenosine receptors in this response. Injection of carrageenan into the pleural cavity induced an acute inflammatory response characterized by leukocyte migration, pleural exudation, and increased release of interleukin-1β and tumor necrosis factor-α in pleural exudates. The treatment with adenosine (0.3-100 mg/kg, i.p.) and inosine (0.1-300 mg/ kg, i.p.) 30 min before carrageenan injection reduced significantly all these parameters analyzed. Our results also demonstrated that A 2A and A 2B receptors seem to mediate the adenosine and inosine effects observed, since pretreatment with selective antagonists of adenosine A 2A (ZM241385) and A 2B (alloxazine) receptors, reverted the inhibitory effects of adenosine and inosine in pleural inflammation. The involvement of A 2 receptors was reinforced with adenosine receptor agonist CGS21680 treatment, since its anti-inflammatory effects were reversed completely and partially with ZM241385 and alloxazine injection, respectively. Moreover, the combined treatment with subeffective dose of adenosine (0.3 mg/kg) and inosine (1.0 mg/kg) induced a synergistic anti-inflammatory effect. Thus, based on these findings, we propose that inosine contributes with adenosine to exert anti-inflammatory effects in pleural inflammation, reinforcing the notion that endogenous nucleosides play an important role in controlling inflammatory diseases. This effect is likely mediated by the activation of adenosine A 2 subtype receptors and inhibition of production or release of pro-inflammatory cytokines.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Anti-inflammatory effects of purine nucleosides, adenosine and inosine, in a mouse model of pleurisy: evidence for the role of adenosine A2 receptors

Lapa

Silva

Cabrini

et al. 2012

Purinergic Signalling

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“…19 A possible explanation for our findings is that small vessels, because of their anatomical position at the blood-tissue interface, play a key role in regulation of extracellular and vascular nucleoside levels. In fact, they possess high-affinity nucleoside transporters 20 and have a high capacity for nucleoside accumulation. 21 Thus, we hypothesize that in MNGIE, deoxynucleotides accumulate in small vessels wall, where they exert their toxic effect.…”

Section: Discussionmentioning

confidence: 99%

Gastrointestinal Dysmotility in Mitochondrial Neurogastrointestinal Encephalomyopathy Is Caused by Mitochondrial DNA Depletion

Giordano

Sebastiani

Giorgio

et al. 2008

The American Journal of Pathology

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Chronic intestinal pseudo-obstruction is a life-threatening condition of unknown pathogenic mechanisms. Chronic intestinal pseudo-obstruction can be a feature of mitochondrial disorders, such as mitochondrial neurogastrointestinal encephalomyopathy (MNGIE), a rare autosomal-recessive syndrome, resulting from mutations in the thymidine phosphorylase gene. MNGIE patients show elevated circulating levels of thymidine and deoxyuridine, and accumulate somatic mitochondrial DNA (mtDNA) defects. The present study aimed to clarify the molecular basis of chronic intestinal pseudoobstruction in MNGIE. Using laser capture microdissection, we correlated the histopathological features with mtDNA defects in different tissues from the gastrointestinal wall of five MNGIE and ten control patients. We found mtDNA depletion, mitochondrial proliferation, and smooth cell atrophy in the external layer of the muscularis propria, in the stomach and in the small intestine of MNGIE patients. In controls, the lowest amounts of mtDNA were present at the same sites, as compared with other layers of the gastrointestinal wall. We also observed mitochondrial proliferation and mtDNA depletion in small vessel endothelial and smooth muscle cells. Thus, visceral mitochondrial myopathy likely causes gastrointestinal dysmotility in MNGIE patients. The low baseline abundance of mtDNA molecules may predispose smooth muscle cells of the muscularis propria external layer to the toxic effects of thymidine and deoxyuridine, and exposure to high circulating levels of nucleosides may account for the mtDNA depletion observed in the small vessel wall. (Am J Pathol

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“…58,23 Extracellular adenosine has a very short half-life in the extracellular space. This is mainly due to its rapid uptake into the intracellular space by nucleoside transporters, 24,34,29 where it is rapidly metabolized into inosine by adenosine deaminase or into AMP by adenosine kinase. 61,28 …”

Section: Brief Review Wwwjasnorgmentioning

confidence: 99%

“…24,23,25 As such, extracellular adenosine production is enhanced during limited oxygen availability 23,26 -29 and is critical to maintaining cellular functions during hypoxia, 30,23,31 or to dampen hypoxia-driven inflammation. [32][33][34]28,17 On the basis of such findings, recent studies in the kidneys implicate extracellular adenosine generation and signaling as pharmacologic targets for protection from ischemia.…”

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confidence: 99%