Adenosine A_2Areceptor activation reduces infarct size in the isolated, perfused mouse heart by inhibiting resident cardiac mast cell degranulation

Abstract

Rork TH, Wallace KL, Kennedy DP, Marshall MA, Lankford AR, Linden J. Adenosine A 2A receptor activation reduces infarct size in the isolated, perfused mouse heart by inhibiting resident cardiac mast cell degranulation. Am J Physiol Heart Circ Physiol 295: H1825-H1833, 2008; doi:10.1152/ajpheart.495.2008.-Mast cells are found in the heart and contribute to reperfusion injury following myocardial ischemia. Since the activation of A 2A adenosine receptors (A 2AARs) inhibits reperfusion injury, we hypothesized that ATL146e (a selective A 2AAR agonist) might protect hearts in part by reducing cardiac mast cell degranulation. Hearts were isolated from five groups of congenic mice: A 2AAR ϩ/ϩ mice, A2AAR Ϫ/Ϫ mice, mast celldeficient (Kit W-sh/W-sh ) mice, and chimeric mice prepared by transplanting bone marrow from A 2AAR Ϫ/Ϫ or A2AAR ϩ/ϩ mice to radiation-ablated A 2AAR ϩ/ϩ mice. Six weeks after bone marrow transplantation, cardiac mast cells were repopulated with Ͼ90% donor cells. In isolated, perfused hearts subjected to ischemia-reperfusion injury, ATL146e or CGS-21680 (100 nmol/l) decreased infarct size (IS; percent area at risk) from 38 Ϯ 2% to 24 Ϯ 2% and 22 Ϯ 2% in ATL146e-and CGS-21680-treated hearts, respectively (P Ͻ 0.05) and significantly reduced mast cell degranulation, measured as tryptase release into reperfusion buffer. These changes were absent in A 2AARϪ/Ϫ hearts and in hearts from chimeric mice with A2AARϪ/Ϫ bone marrow. Vehicle-treated Kit W-sh/W-sh mice had lower IS (11 Ϯ 3%) than WT mice, and ATL146e had no significant protective effect (16 Ϯ 3%). These data suggest that in ex vivo, buffer-perfused hearts, mast cell degranulation contributes to ischemia-reperfusion injury. In addition, our data suggest that A2AAR activation is cardioprotective in the isolated heart, at least in part by attenuating resident mast cell degranulation.Langendorff; tryptase; ATL146e; CGS-21680; bone marrow chimera MAST CELLS CONTRIBUTE to immune responses with both sentinel and effector roles in host defense and inflammation. The activation of mast cells has been found to have protective or deleterious effects in response to tissue infection or injury (22,29). This is due in part to tissue-specific heterogeneity of mast cell function (3, 48). In the heart, degranulation of resident cardiac mast cells mediates injurious effects during experimental ischemia-reperfusion (I/R) injury and myocardial infarction (MI). These deleterious effects are mediated by multiple mechanisms, including a local renin-angiotensin axis (18,26,41), histamine and prostanoid-induced ventricular arrhythmogenesis (36), and the initiation of a cytokine cascade resulting in increased ICAM-1 expression and neutrophil extravasation (13,42). In addition, resident cardiac mast cells contribute to the ventricular hypertrophic response during chronic cardiac volume overload (6,16,32,33). In the isolated heart, oxidative stress from I/R is sufficient to stimulate degranulation of resident cardiac mast cells (13). Mast cell stabilizers such as ketotifen an...

Reduction in myocardial infarct size at 48 hours after brief intravenous infusion of ATL-146e, a highly selective adenosine A2A receptor agonist

“…It is not yet known whether this is also the case in the heart; however, the data presented here demonstrate that ATL164e treatment reduced inflammation in the reperfused zone, as evidenced by a reduction in neutrophil infiltration, compared with vehicle. In a recent study using an isolated, bufferperfused heart model, Rork et al (20) showed that, even in the absence of neutrophils, ATL-146e reduced tissue-resident mast cell degranulation and protected against postischemic myocardial necrosis. Thus current evidence demonstrates that the anti-inflammatory and infarct-sparing effects of A 2A adenosine receptor activation result from inhibition of multiple inflammatory cell types including NKT cells, mast cells, and neutrophils.…”

Transcriptomic effects of adenosine 2A receptor deletion in healthy and endotoxemic murine myocardium

“…In this regard, adenosine 2A receptors (A 2A Rs) may fulfil a broadly suppressive role to limit inflammatory injury in multiple tissues [3][4][5][6] and enhance myocardial resistance to ischaemic/hypoxic insult, presenting a potentially useful therapeutic target [3,7]. In heart, this G protein-coupled receptor (GPCR) influences coronary tone and angiogenesis, cardiac contractility, fibroblast growth and fibrosis and may mediate protection via ischaemic pre-and postconditioning [8][9][10]. Inflammatory modulation contributes to this latter cardioprotection [9][10][11], together with the regulation of myocyte kinase signals to limit oxidative stress, mitochondrial dysfunction and cell death [12][13][14].…”

“…In heart, this G protein-coupled receptor (GPCR) influences coronary tone and angiogenesis, cardiac contractility, fibroblast growth and fibrosis and may mediate protection via ischaemic pre-and postconditioning [8][9][10]. Inflammatory modulation contributes to this latter cardioprotection [9][10][11], together with the regulation of myocyte kinase signals to limit oxidative stress, mitochondrial dysfunction and cell death [12][13][14]. However, impacts of the A 2A R on integrated myocardial responses to uncontrolled inflammation, and the mechanisms underlying such effects, remain to be elucidated.…”

Pulmonary Transplantation and Ischemia-Reperfusion Injury

“…Adenosine is an endogenous mediator that generally serves as a cytoprotective modulator in response to various stress stimuli, and the protective effects of adenosine in the setting of organ IR injury have been shown in various studies (Day, et al, 2005(Day, et al, , 2006Reece, et al, 2008;Rork, et al, 2008). Adenosine signals through 4 subtypes of the G protein-coupled receptors, A 1 R, A 2A R, A 2B R, and A 3 R, all of which are expressed in the lung.…”