The A2B adenosine receptor protects against inflammation and excessive vascular adhesion

Yang, Dan; Zhang, Ying; Nguyen, Hao G.; Koupenova, Milka; Chauhan, Anil K.; Makitalo, Maria; Jones, Matthew R.; Hilaire, Cynthia St.; Seldin, David C.; Toselli, Paul; Lamperti, Edward D.; Schreiber, Barbara M.; Gavras, Haralambos; Wagner, Denisa D.; Ravid, Katya

doi:10.1172/jci27933

Cited by 321 publications

(458 citation statements)

References 59 publications

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“…In addition, the antiinflammatory effects of A 2B have already been described in literature. Yang and colleagues reported that A 2B null mice present augmentation of pro-inflammatory cytokine levels, such as TNF-α, upregulation of vascular adhesion proteins, and leukocyte migration in response to lipopolysaccharide (LPS)-induced acute inflammation [50]. Thus, our study provides the first evidence that adenosine and inosine can activate adenosine A 2A and A 2B receptors in acute pleural inflammation, and therefore, being important regulators of this process.…”

Section: Discussionsupporting

confidence: 55%

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: Discussionsupporting

confidence: 55%

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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“…To examine whether the low-affinity A2bARs have an effect on vascular phenotypes, we generated an A2bAR KO/reporter gene knockin mouse model (10). Our earlier studies demonstrated that the A2bARs are notably expressed in vascular cells and macrophages and protect against excessive vascular adhesion (10), suggesting that A2bARs mediate a protective effect on the vasculature.…”

Section: Inflammation ͉ Cxcr4mentioning

confidence: 99%

The A2b adenosine receptor protects against vascular injury

Yang

Koupenova

McCrann

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

114

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The A2b adenosine receptor (A2bAR) is highly abundant in bone marrow macrophages and vascular smooth muscle cells (VSMC). To examine the functional significance of this receptor expression, we applied a femoral artery injury model to A2bAR knockout (KO) mice and showed that the A2bAR prevents vascular lesion formation in an injury model that resembles human restenosis after angioplasty. While considering related mechanisms, we noted higher levels of TNF-␣, an up-regulator of CXCR4, and of VSMC proliferation in the injured KO mice. In accordance, CXCR4, which is known to attract progenitor cells during tissue regeneration, is up-regulated in lesions of the KO mice. In addition, aortic smooth muscle cells derived from A2bAR KO mice display greater proliferation in comparison with controls. Bone marrow transplantation experiments indicated that the majority of the signal for lesion formation in the null mice originates from bone marrow cells. Thus, this study highlights the significance of the A2bAR in regulating CXCR4 expression in vivo and in protecting against vascular lesion formation.inflammation ͉ CXCR4

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“…For these reasons caffeine is generally believed to act on A 1 R and A 2A R to exert most of its effects, at least when given in lower doses (18). However, a recent study showed that A 2B R knockout (A 2B RKO) mice have elevated cytokines, vascular adhesion molecules, and leukocyte adherence (49), indicating that A 2B R is probably also activated by endogenous adenosine. This could indicate that at some sites local adenosine concentrations may be high enough to activate A 2B R.…”

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confidence: 99%

Physiological roles of A₁ and A_2A adenosine receptors in regulating heart rate, body temperature, and locomotion as revealed using knockout mice and caffeine

Yang

Chen²,

Fredholm³

2009

American Journal of Physiology-Heart and Circulatory Physiology

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Yang JN, Chen JF, Fredholm BB. Physiological roles of A1 and A2A adenosine receptors in regulating heart rate, body temperature, and locomotion as revealed using knockout mice and caffeine. Am J Physiol Heart Circ Physiol 296: H1141-H1149, 2009. First published February 13, 2009 doi:10.1152/ajpheart.00754.2008.-Heart rate (HR), body temperature (Temp), locomotor activity (LA), and oxygen consumption (O2C) were studied in awake mice lacking one or both of the adenosine A 1 or A2A receptors (A1R or A2AR, respectively) using telemetry and respirometry, before and after caffeine administration. All parameters were lower during day than night and higher in females than males. When compared with wild-type (WT) littermates, HR was higher in male A 1R knockout (A1RKO) mice but lower in A2ARKO mice and intermediate in A1-A2AR double KO mice. A single dose of an unselective ␤-blocker (timolol; 1 mg/kg) abolished the HR differences between these genotypes. Deletion of A 1Rs had little effect on Temp, whereas deletion of A 2ARs increased it in females and decreased it in males. A 1-A2ARKO mice had lower Temp than WT mice. LA was unaltered in A 1RKO mice and lower in A 2ARKO and A1-A2ARKO mice than in WT mice. Caffeine injection increased LA but only in mice expressing A 2AR. Caffeine ingestion also increased LA in an A 2AR-dependent manner in male mice. Caffeine ingestion significantly increased O 2C in WT mice, but less in the different KO mice. Injection of 30 mg/kg caffeine decreased Temp, especially in KO mice, and hence in a manner unrelated to A 1R or A 2AR blockade. Selective A2B antagonism had little or no effect. Thus A 1R and A2AR influence HR, Temp, LA, and O2C in mice in a sex-dependent manner, indicating effects of endogenous adenosine. The A2AR plays an important role in the modulation of O2C and LA by acute and chronic caffeine administration. There is also evidence for effects of higher doses of caffeine being independent of both A 1R and A2AR. diurnal rhythm; metabolic rate; locomotor activity; adenosine; telemetry CAFFEINE (1,3,7-trimethylxanthine), the most widely consumed stimulant in the world, acts as a competitive antagonist of adenosine receptors (ARs) (18). It is much more potent on three of the known receptors, A 1 , A 2A , and A 2B (A 1 R, A 2A R, and A 2B R, respectively) than on the fourth, the A 3 R (17). Since a competitive antagonist will have effects only when and where receptors are activated by an agonist, it is relevant that endogenous agonist adenosine is more potent on A 1 R and A 2A R than on A 2B R. The potency of adenosine as an agonist in addition depends on the density of the receptors (16). The levels of adenosine are low under physiological condition but are sufficient to partially activate A 1 R, A 2A R, and A 3 Rs where the receptors are abundantly expressed. For these reasons caffeine is generally believed to act on A 1 R and A 2A R to exert most of its effects, at least when given in lower doses (18). However, a recent study showed that A 2B R knockout (A 2B RKO) mice have e...

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The A2B adenosine receptor protects against inflammation and excessive vascular adhesion

Cited by 321 publications

References 59 publications

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

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

The A2b adenosine receptor protects against vascular injury

Physiological roles of A₁ and A_2A adenosine receptors in regulating heart rate, body temperature, and locomotion as revealed using knockout mice and caffeine

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