Regulation of cell proliferation by the guanosine-adenosine mechanism: role of adenosine receptors

Abstract

A recent study (American Journal of Physiology-Cell Physiology 304: C406–C421, 2013) suggests that extracellular guanosine increases extracellular adenosine by modifying the disposition of extracellular adenosine (“guanosine-adenosine mechanism”) and that the guanosine-adenosine mechanism is not mediated by classical adenosine transport systems (SLC28 and SLC29 families) nor by classical adenosine-metabolizing enzymes. The present investigation had two aims: 1) to test the hypothesis that the “guanosine-adenosine mechanism” affects cell proliferation; and 2) to determine whether the transporters SLC19A1, SLC19A2, SLC19A3 or SLC22A2 (known to carrier guanosine analogues) might be responsible for the guanosine-adenosine mechanism. In the absence of added adenosine, guanosine had little effect on the proliferation of coronary artery vascular smooth muscle cells (vascular conduit cells) or preglomerular vascular smooth muscle cells (vascular resistance cells). However, in the presence of added adenosine (3 or 10 μmol/L), guanosine (10 to 100 μmol/L) decreased proliferation of both cell types, thus resulting in a highly significant (p<0.000001) interaction between guanosine and adenosine on cell proliferation. The guanosine-adenosine interaction on cell proliferation was abolished by 1,3-dipropyl-8-(p-sulfophenyl)xanthine (adenosine receptor antagonist). Guanosine (30 μmol/L) increased extracellular levels of adenosine when adenosine (3 μmol/L) was added to the medium. This effect was not reproduced by high concentrations of methotrexate (100 μmol/L), thiamine (1000 μmol/L), chloroquine (1000 μmol/L) or acyclovir (10,000 μmol/L), archetypal substrates for SLC19A1, SLC19A2, SLC19A3, and SLC22A2, respectively; and guanosine still increased adenosine levels in the presence of these compounds. Conclusion: The guanosine-adenosine mechanism affects cell proliferation and is not mediated by SLC19A1, SLC19A2, SLC19A3 or SLC22A2.

Guanosine inhibits LPS-induced pro-inflammatory response and oxidative stress in hippocampal astrocytes through the heme oxygenase-1 pathway

“…Because some effects of guanosine have been shown to be mediated by adenosinergic system [44][45][46], the role of adenosine and/or caffeine (adenosine receptor antagonist) in LPSinduced inflammatory response was also evaluated. Interestingly, adenosine (100 and 1000 μM) did not prevent the increase in cytokine release that occurred after LPS exposure (Table 1).…”

Guanosine and its role in neuropathologies

“…It was demonstrated that, although guanosine is not considered an effective ligand for P1 receptors [41,81], antagonists of these receptors are able to, at least partially, inhibit the proliferative [41,45] and antiinflammatory [82,83] activities elicited by this nucleoside. This evidence suggests that extracellular guanosine may contribute to cell signaling, through an indirect mechanism involving the adenosinergic system [84,85]. However, it should be noted that many of the effects of guanosine persist in the presence of P1 antagonists [43], indicating that this nucleoside also acts by distinct mechanisms that are independent of the adenosinergic system.…”

Adenosine Attenuates Human Coronary Artery Smooth Muscle Cell Proliferation by Inhibiting Multiple Signaling Pathways That Converge on Cyclin D

“…Adenosine appears to be one such factor. Adenosine potently inhibits the proliferation of rat renal preglomerular VSMCs 2, 3 , rat4–8 and human 9 aortic VSMCs, rat 3, 10 and human 11 glomerular mesangial cells, and rat cardiac fibroblasts 12–16 ; yet adenosine stimulates the proliferation of rat aortic 17 , rat renal microvascular 18 , and porcine coronary 17 vascular endothelial cells, as well as human 18 renal epithelial cells. In addition, adenosine has several other desirable tissue-protecting actions such as promoting neovascularization 19–21 and preventing and reducing inflammation and hypoxia 22–27 .…”