Adenosine A 2 B Receptor Agonism Inhibits Neointimal Lesion Development After Arterial Injury in Apolipoprotein E – Deficient Mice

Adenosine is a ubiquitous endogenous molecule involved in inflammatory responses, in which adenosine receptors play an important role. The adenosine receptor family consists of 4 G protein–coupled receptors (A 1 , A 2A , A 2B , and A 3 ), which have been implicated in a number of inflammatory and immune diseases such as asthma and arthritis. The low-affinity A 2B adenosine receptor (A 2B R) is expressed on a number of immune cells, such as macrophages, mast cells, and cells of the vessel wall including fibroblasts, smooth muscle cells (SMCs), and endothelial cells. In most immune cells, A 2B receptor activation induces an inflammatory response, for example by inducing the release of Interleukin (IL)-6. Also, mast cells can be activated via the A 2B receptor. In contrast, Yang et al recently demonstrated that the A 2B receptor can also protect against inflammation. In A 2B receptor–deficient mice, IL-6 levels and tumor necrosis factor-α were higher as compared with wild-type mice, both under basal conditions and after lipopolysaccharide stimulation. Furthermore, A 2B receptor deficiency enhances the expression of adhesion molecules, as well as leukocyte adhesion and rolling and was shown to increase atherosclerotic lesion development. In another study, A 2B receptor–deficient mice were subjected to femoral artery wire injury, after which it was demonstrated that deficiency in the A 2B receptor leads to enhanced neointimal thickening. This was probably caused by a combined increase in the systemic inflammation, presumably via the CXCR4 chemokine receptor, and in SMC proliferation. Previously, it had already been shown that adenosine inhibits the growth of SMCs via activation of the A 2B receptor. Restenosis, which is defined as the recurrence of atherosclerosis after percutaneous transluminal coronary an gioplasty, is one of the major clinical disadvantages of the treatment of cardiovascular disorders, as ≈30% of the patients that undergo percutaneous transluminal coronary angioplasty develop restenosis within 6 months after surgery. Potential therapeutic strategies have been explored for years already, such as bare metal or drug-eluting stent placement, but still a substantial number of patients