Adenosine A _2A Receptor Stimulation Reduces Inflammation and Neointimal Growth in a Murine Carotid Ligation Model

Abstract

Abstract-Endothelial activation and leukocyte recruitment are early events in atherosclerosis and the vascular response to injury. Adenosine has anti-inflammatory effects on leukocytes and endothelial cells mediated through its A 2A receptor. We tested the hypothesis that A 2A activation would reduce inflammation and neointimal formation in a murine carotid ligation model. Before injury, mice were randomized to a 7-day subcutaneous infusion of a specific A 2A receptor agonist (ATL-146e, 0.004 g/kg per minute), vehicle control, ATL-146e plus ZM241385 (a selective A 2A antagonist), or ZM241385 alone. Leukocyte recruitment and adhesion molecule expression were assessed at early time points, and the neointimal area was measured at 14 and 28 days after injury. Compared with control mice, ATL-146e-treated mice had significantly less neutrophil and macrophage recruitment and vascular cell adhesion molecule-1, intercellular adhesion molecule-1, and P-selectin expression in the first 7 days after injury. Neointimal area was markedly and persistently reduced by 80% at 14 and 28 days, despite termination of ATL infusion at 7 days. ATL-146eϩZM241385-treated and ZM241385-treated animals had neointimal areas similar to those of control animals, confirming that the observed effects of ATL-146e were mediated specifically by the A 2A receptor. These data demonstrate that novel stimulation of adenosine A 2A receptors can inhibit early inflammatory processes that are important in neointimal formation after vascular injury.

Protective effects of adenosine A2A receptor agonist in ventilator-induced lung injury in rats

“…In ischemia reperfusion models, the use of A 2A receptor agonists resulted in a decrease in macrophage activation and adhesion molecular expression on endothelial cells, blockage of endothelial-neutrophil interactions, and attenuation of vascular derangement (11,12,(17)(18)(19)(20)(21). The administration of the A 2A receptors agonist CGS-21680 has been shown to ameliorate lung injury in animal models of ischemia and reperfusion (12,17).…”

“…The A 2A R expressed on leukocytes and lung displays high affinity for adenosine (8). Several studies have shown that activation of A 2A receptor is protective against ischemia/reperfusion injury by decreasing the expression of endothelial adhesion molecules and the production of cytokines and reactive oxygen species (17)(18)(19)(20)(21). We thus hypothesized that a pharmacologic intervention with an A 2A R agonist protects the lung from injury in a two-hit model of HSR followed by mechanical ventilation.…”

Neuroprotection by adenosine in the brain: From A1 receptor activation to A2A receptor blockade

“…In fact, adenosine is a potent anti-inflammatory agent with A 2A Rs triggering BOFF^signals in activated immune cells, which constitutes one of the most fundamental and immediate tissue-protecting mechanisms (reviewed in [295,296]). A 2A R agonists were even named Bthe most potent anti-inflammatory drug known to mankind.^Ac-cordingly, activation of A 2A Rs has been shown to confer a robust protection against tissue damage from ischemiaYreperfusion injury in different organ such as heart [297Y299], blood vessels [300], kidney [301,302], liver [303,304], lung [305,306], joints [307], skin [308,309], and even in the spinal cord [310,311] and in the brain following hemorrhage [312] or acute infection [313]. Thus, it is the activation (rather the blockade) of A 2A Rs that confers protection against damage triggered by inflammation in peripheral tissues, precisely the opposite of what is observed in the damaged adult brain.…”

The A2b adenosine receptor protects against vascular injury

“…Interestingly, an in vivo model of smooth muscle cell proliferation revealed that an A2 receptor agonist, 2-octynyladenosine, inhibited neointima formation (8). Furthermore, it has been reported that A2aAR activation reduces neointimal formation in a carotid ligation injury model (9). Adenosine receptors also play a major role in several inflammation-associated processes by inhibiting immune activation and preventing excessive tissue damage.…”