Adenosine: Mechanisms of Cytotoxicity and Vasculoprotection

This is a really terrific article on adenosine in the context of ischemia and endothelial cell proliferation. In general, substances (growth factors, nutrients, or other compounds) that endothelial cell proliferation have the potential, under the correct circumstances, to be vasculoprotective and antiatherogenic, and things that enhance vascular smooth muscle cell proliferation can lead to hypertension or atherogenesis, etc. This article talks about the way adenosine enhances endothelial cell proliferation at extracellular concentrations up to slightly less than 1 mM, which is supraphysiological, and then tends to cause cytotoxic effects (endothelial cell apoptosis) at concentrations above 1 mM:

http://ajpregu.physiology.org/cgi/content/full/289/2/R283
(pubmed: http://www.ncbi.nlm.nih.gov/pubmed/16014444?dopt=Abstract)

This is relevant to the vasculoprotective effects of things like physical exercise, because exercise causes the muscles to export purines into the blood. But the graph the author includes, showing the concentration-dependence of the pro-apoptotic effects of adenosine, is really important for understanding the interactions of locally-produced adenosine with S-adenosylhomocysteine hydrolase activity. The pro-apoptotic effects of adenosine have generally been shown to be mediated by inhibition of S-adenosylhomocysteine hydrolase activity, but this effect doesn't seem to occur until the extracellular adenosine concentration is around 1 mM or higher. Even though the authors of this article use a 1 mM adenosine concentration, the finding that SAHH inhibition mediates its apoptotic effects in cultured hepatocytes is important for research on, or understanding of, the effects and safety of exogenous purines:

http://www.ncbi.nlm.nih.gov/pubmed/17097637

That's still a great article, and I was looking at that today. The implication is that, if exogenous nucleotides (particularly purines, in this context) were used for some sort of therapeutic purpose, one would want to maximize the methionine synthase-mediated decrease in the inwardly-directed transmembrane adenosine gradient, such as with a reduced folate, to minimize the potential for SAHH inhibition. I saw some reference in an article that imply that adenosine has the potential to cause mechanism-based inhibition of SAHH, but I'll have to read up on that. I thought it was just allosteric inhibition.

I actually haven't looked through this article yet, but it's on the transmembrane adenosine gradient in general and looks at the ratio of intracellular to extracellular adenosine levels:

http://circ.ahajournals.org/cgi/content/full/99/15/2041
(http://www.ncbi.nlm.nih.gov/pubmed/10209010?dopt=Abstract)

This is another one that's good:

http://cardiovascres.oxfordjournals.org/cgi/content/full/59/2/271
(pubmed: http://www.ncbi.nlm.nih.gov/pubmed/12909310?dopt=Abstract)