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Department of Medicine, University of Virginia, Charlottesville, Virginia
Abstract
Adenosine promotes tissue protection and repair through four general modes of action: increased oxygen supply/demand ratio, preconditioning, anti-inflammatory effects, and stimulation of angiogenesis. A novel means by which adenosine stimulates angiogenesis is the topic of the article by Desai et al. in the April 2005 issue of Molecular Pharmacology. The report demonstrates that agonists of A2A adenosine receptors inhibit the release of the anti-angiogenic factor thrombospondin 1. Multiple cell types and all four adenosine receptors participate in these responses. Exploiting these effects of adenosine has great therapeutic potential.
Adenosine produced in hypoxic, ischemic, or inflamed environments reduces tissue injury and promotes repair by several receptor-mediated mechanisms. The intracellular production of adenosine is increased during hypoxia or ischemia and transported across cell membranes by various transporters (Thorn and Jarvis, 1996). In addition, adenine nucleotides are released from nerves, platelets, and other cell types in granules or through various channels (Dutta et al., 2004; Fabbro et al., 2004) and metabolized to adenosine primarily by ecto-apyrase (CD39) and ecto-5'-nucleotidase (CD73) (Koszalka et al., 2004). Adenosine signals through four widely expressed G protein coupled receptors: A1, A2A, A2B, and A3. There are four general modes of responses by which adenosine receptor activation protects tissues and facilitates tissue repair; these are summarized in Table 1: increased oxygen supply/demand ratio, preconditioning, anti-inflammatory effects, and stimulation of angiogenesis. A novel means by which adenosine stimulates angiogenesis is the topic of the article by Desai et al. (2005) in this issue. These new findings add to accumulating evidence that all four adenosine receptor subtypes participate in various ways to protect and facilitate regeneration of injured tissues.
Increases in Oxygen Supply/Demand Ratio
Tissue protection by adenosine was first attributed to its cardiovascular effects. Vascular smooth muscle of coronary arteries was found to have a high density of A2A adenosine receptors and to be very sensitive to adenosine partly because of spare receptors (Shryock et al., 1998). Adenosine produces vasodilation to increase oxygen delivery to the hypoxic heart. Blood vessels in other tissues are generally less sensitive to adenosine than coronary arteries but also dilate in response to adenosine through a combination of A2A and A2B receptors. Adenosine also acts to reduce oxygen demand in excitable tissues such as heart and neurons as a result of the activation of A1 receptors that increase neuronal conductance to potassium ions or decrease conductance to calcium ions (Dolphin et al., 1986). In addition, activation of A1 receptors on sympathetic nerve terminals reduces the release of norepinephrine, resulting in decreased cardiac output and decreased peripheral vascular resistance (Burgdorf et al., 2001, 2005). It has been shown recently that hypoxia increases the sensitivity of endothelial cells to adenosine in part by causing a rapid induction of A2B receptor mRNA (Eltzschig et al., 2003).
Ischemic Preconditioning and Postconditioning
Adenosine also protects tissues through its role in ischemic preconditioning—defined as a reduction in tissue infarct size during a prolonged ischemic episode as a result of a short prior episode of ischemia. Preconditioning has been most extensively studied in the heart but also occurs in other tissues. Adenosine produced in the ischemic heart participates in this response by activating A1 and A3 receptors, protein kinase C, and mitochondrial KATP channels (Miura et al., 2000; De et al., 2002). It has been demonstrated recently that "postconditioning", a brief period of ischemia after prolonged ischemia, can reduce myocardial inflammation and infarct size (Zhao et al., 2003). It is likely that adenosine released during postconditioning contributes to inhibition of inflammation, probably as a result of activation of A2A receptors on inflammatory cells.
Anti-Inflammatory Responses. Many recent studies indicate that adenosine acting on A2A receptors can powerfully inhibit inflammation and reperfusion injury. The A2A adenosine receptor is found on most bone-marroweCderived cells and produces cellular effects that in general inhibit inflammation. The cellular responses seem to be mediated predominately by cyclic AMP and result in inhibition of oxidative burst in neutrophils (Fredholm et al., 1996), reduced TNF release by monocytes (Link et al., 2000), reduced platelet activation (Hourani, 1996), and inhibition of lymphocyte activation (Lappas et al., 2005). In aggregate, these responses prevent the release of pro-inflammatory cytokines and oxygen radicals, prevent endothelial cell activation, and greatly reduce microvascular occlusion, which can exacerbate tissue injury during reperfusion of previously ischemic tissues.
A2B Receptors are Proinflammatory. Both A2A and A2B receptors couple to the heterotrimeric G protein, Gs; in many cell types, however, A2B receptors have been found to be dually coupled to Gs and Gq. Signaling through Gq results in calcium mobilization and activation of phospholipase C and mitogen-activated protein kinase (Gao et al., 1999). This signaling pathway seems to be responsible for pro-inflammatory actions of adenosine mediated by A2B receptors that results in facilitation by adenosine of antigen-induced deregulation of canine or human but not rodent mast cells (Feoktistov and Biaggioni, 1995; Auchampach et al., 1997). In addition, activation of A2B receptors has been shown to increase the release of interleukin 6 from epithelial cells, astrocytes, and fibroblasts (Schwaninger et al., 1997; Sitaraman et al., 2001; Zhong et al., 2005). Hence, the activation of adenosine receptors is not invariably protective of tissues. In fact, A2B blockers may be useful as anti-inflammatory agents.
Angiogenesis
In addition to protecting tissues, adenosine has long been known to stimulate angiogenesis, which is necessary for tissue repair (Teuscher and Weidlich, 1985; Dusseau et al., 1986). As is the case for tissue protection by adenosine, multiple adenosine receptor subtypes participate in the stimulation of angiogenesis. Activation of the A1 receptors powerfully stimulates angiogenesis in vivo by an as-yet-undefined mechanism (Linden et al., 2003). Stimulation of angiogenesis also is caused in part by activation of A2B receptors on endothelial cells (Feoktistov et al., 2002) and A2B or A3 receptors on mast cells (Feoktistov et al., 2003) that induce the release of angiogenic factors including VEGF. The report by Desai et al. (2005) in this issue describes another means by which adenosine receptors on human umbilical vein endothelial cells stimulate angiogenesis. Adenosine inhibits the release of the anti-angiogenic protein thrombospondin 1, resulting in increasing vascular tube formation. Blockade of this response by the A2A-selective antagonist ZM241385 is not surmountable by high doses of A2A agonists, but despite this peculiarity, the pharmacological profile of the response suggests that it is mediated by the A2A receptor. Desai et al. (2005) also show that in the presence of antibodies to TSP1 or CD36, the receptor for TSP1, A2A agonists fail to stimulate vascular tube formation. These results indicate that vascular tube formation by adenosine A2A receptor activation is largely mediated by suppression of TSP1 secretion.
Conclusion
Tissue protection and regeneration by adenosine is mediated by multiple different cells types and involves participation of all four adenosine receptor subtypes. Fully understanding and exploiting these protective and regenerative mechanisms has great clinical potential.
doi:10.1124/mol.105.011783.
Please see the related article on page page 1406.
References
Auchampach JA, Jin J, Wan TC, Caughey GH, and Linden J (1997) Canine mast cell adenosine receptors: cloning and expression of the A3 receptors and evidence that degranulation is mediated by the A2b receptor. Mol Pharmacol 52: 846eC860.
Belardinelli L, Shryock JC, Snowdy S, Zhang Y, Monopoli A, Lozza G, Ongini E, Olsson RA, and Dennis DM (1998) The A2A adenosine receptor mediates coronary vasodilation. J Pharmacol Exp Ther 284: 1066eC1073.
Burgdorf C, Richardt D, Kurz T, Seyfarth M, Jain D, Katus HA, and Richardt G (2001) Adenosine inhibits norepinephrine release in the postischemic rat heart: the mechanism of neuronal stunning. Cardiovasc Res 49: 713eC720.
Burgdorf C, Schutte F, Kurz T, Dendorfer A, and Richardt G (2005) Adenylyl cyclase-dependent inhibition of myocardial norepinephrine release by presynaptic adenosine a1-receptors. J Cardiovasc Pharmacol 45: 1eC3.
Day YJ, Marshall MA, Huang L, McDuffie MJ, Okusa MD, and Linden J (2004) Protection from ischemic liver injury by activation of A2a adenosine receptors during reperfusion: inhibition of chemokine induction. Am J Physiol 286: G285eCG293.
Day YJ, Huang L, McDuffie MJ, Rosin DL, Ye H, Chen JF, Schwarzschild MA, Fink JS, Linden J, and Okusa MD (2003) Renal protection from ischemia mediated by A2A adenosine receptors on bone marrow-derived Cells. J Clin Investig 112: 883eC891.
De JR, Out M, Maas WJ, and De Jong JW (2002) Preconditioning of rat hearts by adenosine A1 or A3 receptor activation. Eur J Pharmacol 441: 165eC172.
Desai A, Victor-Vega C, Gadangi Swathi, Montesinos MC, Chu CC, and Cronsteiny BN (2005) Adenosine A2A receptor stimulation increases angiogenesis by down-regulating production of the antiangiogenic matrix protein thrombospondin 1. Mol Pharmacol 67: 1406eC1413.
Dhalla AK, Shryock JC, Shreeniwas R, and Belardinelli L (2003) Pharmacology and therapeutic applications of A1 adenosine receptor ligands. Curr Top Med Chem 3: 369eC385.
Dolphin AC, Forda SR, and Scott RH (1986) Calcium-dependent currents in cultured rat dorsal root ganglion neurones are inhibited by an adenosine analogue. J Physiol 373: 47eC61.
Dunwiddie TV and Masino SA (2001) The role and regulation of adenosine in the central nervous system. Annu Rev Neurosci 24: 31eC55.
Dusseau JW, Hutchins PM, and Malbasa DS (1986) Stimulation of angiogenesis by adenosine on the chick chorioallantoic membrane. Circ Res 59: 163eC170.
Dutta AK, Sabirov RZ, Uramoto H, and Okada Y (2004) Role of ATP-conductive anion channel in ATP release from neonatal rat cardiomyocytes in ischaemic or hypoxic conditions. J Physiol 559: 799eC812.
Eltzschig HK, Ibla JC, Furuta GT, Leonard MO, Jacobson KA, Enjyoji K, Robson SC, and Colgan SP (2003) Coordinated adenine nucleotide phosphohydrolysis and nucleoside signaling in posthypoxic endothelium: role of ectonucleotidases and adenosine A2B receptors. J Exp Med 198: 783eC796.
Fabbro A, Skorinkin A, Grandolfo M, Nistri A, and Giniatullin R (2004) Quantal release of ATP From clusters of PC12 cells. J Physiol 560: 505eC517.
Feoktistov I and Biaggioni I (1995) Adenosine A2b receptors evoke interleukin-8 secretion in human mast cells—an enprofylline-sensitive mechanism with implications for asthma. J Clin Investig 96: 1979eC1986.
Feoktistov I, Goldstein AE, Ryzhov S, Zeng D, Belardinelli L, Voyno-Yasenetskaya T, and Biaggioni I (2002) Differential expression of adenosine receptors in human endothelial cells: role of A2B receptors in angiogenic factor regulation. Circ Res 90: 531eC538.
Feoktistov I, Ryzhov S, Goldstein AE, and Biaggioni I (2003) Mast cell-mediated stimulation of angiogenesis: cooperative interaction between A2B and A3 adenosine receptors. Circ Res 92: 485eC492.
Fredholm BB, Zhang Y, and van der Ploeg I (1996) Adenosine A2A receptors mediate the inhibitory effect of adenosine on formyl-Met-Leu-Phe-stimulated respiratory burst in neutrophil leucocytes. Naunyn-Schmiedeberg's Arch Pharmacol 354: 262eC267.
Gao Z, Chen T, Weber MJ, and Linden J (1999) A2B adenosine and P2Y2 receptors stimulate mitogen-activated protein kinase in human embryonic kidney-293 cells: cross-talk between cyclic AMP and protein kinase C pathways. J Biol Chem 274: 5972eC5980.
Glover DK, Riou LM, Ruiz M, Sullivan GW, Linden J, Rieger JM, Macdonald TL, Watson DD, and Beller GA (2005) Reduction of infarct size and post-ischemic inflammation from a highly selective adenosine A2A receptor agonist, ATL-146E, in reperfused canine myocardium. Am J Physiol, in press.
Hourani SM (1996) Purinoceptors and platelet aggregation. J Auton Pharmacol 16: 349eC352.
Koszalka P, Ozuyaman B, Huo Y, Zernecke A, Flogel U, Braun N, Buchheiser A, Decking UK, Smith ML, Sevigny J, Gear A, et al. (2004) Targeted Disruption of Cd73/ecto-5'-nucleotidase alters thromboregulation and augments vascular inflammatory response. Circ Res 95: 814eC821.
Lappas CM, Rieger JM, and Linden J (2005) A2A adenosine receptor induction inhibits IFN- production in murine CD4+ T cells. J Immunol 174: 1073eC1080.
Lasley RD, Jahania MS, and Mentzer RM (2001) Beneficial effects of adenosine A2A agonist Cgs-21680in infarcted and stunned porcine myocardium. Am J Physiol 280: H1660eCH1666.
Linden J, Tucker AL, Price R, and Youkey R (2003) Use of selective A1 receptor agonists, antagonists and allosteric enhancers to manipulate angiogenesis. US Patent Application 20030212082.
Link AA, Kino T, Worth JA, McGuire JL, Crane ML, Chrousos GP, Wilder RL, and Elenkov IJ (2000) Ligand-activation of the adenosine A2a receptors inhibits IL-12 production by human monocytes. J Immunol 164: 436eC442.
Miura T, Liu Y, Kita H, Ogawa T, and Shimamoto K (2000) Roles of mitochondrial ATP-sensitive K channels and PKC in anti-infarct tolerance afforded by adenosine A1 receptor activation. J Am Coll Cardiol 35: 238eC245.
Ngai AC, Coyne EF, Meno JR, West GA, and Winn HR (2001) Receptor subtypes mediating adenosine-induced dilation of cerebral arterioles. Am J Physiol 280: H2329eCH2335.
Ohta A and Sitkovsky M (2001) Role of G-protein-coupled adenosine receptors in downregulation of inflammation and protection from tissue damage. Nature (Lond) 414: 916eC920.
Peirce SM, Skalak TC, Rieger JM, MacDonald TL, and Linden J (2001) Selective A2A adenosine receptors activation reduces skin pressure ulcer formation and inflammation. Am J Physiol 281: H67eCH74.
Reece TB, Okonkwo DO, Ellman PI, Warren PS, Smith RL, Hawkins AS, Linden J, Kron IL, Tribble CG, and Kern JA (2004) The evolution of ischemic spinal cord injury in function, cytoarchitecture and inflammation and the effects of adenosine A2A receptor activation. J Thorac Cardiovasc Surg 128: 925eC932.
Ross SD, Tribble CG, Linden J, Gangemi JJ, Lanpher BC, Wang AY, and Kron IL (1999) Selective adenosine-A2A activation reduces lung reperfusion injury following transplantation. J Heart Lung Transplant 18: 994eC1002.
Schwaninger M, Neher M, Viegas E, Schneider A, and Spranger M (1997) Stimulation of interleukin-6secretion and gene transcription in primary astrocytes by adenosine. J Neurochem 69: 1145eC1150.
Shryock JC, Snowdy S, Baraldi PG, Cacciari B, Spalluto G, Monopoli A, Ongini E, Baker SP, and Belardinelli L (1998) A2A-adenosine receptor reserve for coronary vasodilation. Circulation 98: 711eC718.
Sitaraman SV, Merlin D, Wang L, Wong M, Gewirtz AT, Si-Tahar M, and Madara JL (2001) Neutrophil-epithelial crosstalk at the intestinal lumenal surface mediated by reciprocal secretion of adenosine and IL-6. J Clin Investig 107: 861eC869.
Teuscher E and Weidlich V (1985) Adenosine nucleotides, adenosine and adenine as angiogenesis factors. Biomed Biochim Acta 44: 493eC495.
Thorn JA and Jarvis SM (1996) Adenosine transporters. Gen Pharmacol 27: 613eC620.
Zhao ZQ, Corvera JS, Halkos ME, Kerendi F, Wang NP, Guyton RA and Vinten-Johansen J (2003) Inhibition of myocardial injury by ischemic postconditioning during reperfusion: comparison with ischemic preconditioning. Am J Physiol 285: H579eCH588.
Zhong H, Belardinelli L, Maa T, and Zeng D (2005) Synergy between A2B adenosine receptors and hypoxia in activating human lung fibroblasts. Am J Respir Cell Mol Biol 32: 2eC8.