Netrin-1/A2B adenosine signaling in cardioprotection by ischemic preconditioning
Final Report Abstract
Cardiac ischemia-reperfusion injury (IR) represents a major cause of cardiac tissue injury. Adenosine signaling dampens inflammation during cardiac IR. Here, we investigated the role of the adenosine A2b-receptor (A2BAR) on inflammatory cells during cardiac IR. To study A2BAR signaling on inflammatory cells, we transplanted wildtype (WT) bone marrow (BM) into A2BAR-/- mice or A2BAR-/- BM into WT mice. To study the role of polymorphonuclear leukocytes (PMNs), neutrophil-depleted WT mice were treated with an A2BAR agonist. Following treatments, mice were exposed to 60 minutes of myocardial ischemia and 120 minutes of reperfusion. Infarct sizes and Troponin-I levels were determined by triphenyltetrazolium chloride staining and ELISA, respectively. Transplantation of WT-BM into A2BAR-/- mice decreased infarct sizes by 19±4% and Troponin-I by 87.5±25.3ng/ml (n=6). Transplantation of A2BAR-/- BM into WT mice increased infarct sizes by 20±3% and Troponin-I levels by 69.7±17.9ng/ml (n=6). Studies on the reperfused myocardium revealed PMNs as dominant cell type. PMN-depletion or A2BAR agonist treatment reduced infarct sizes by 30±11% or 26±13% (n=4), however the combination of both did not reveal further cardioprotection. Cytokine profiling showed significantly higher cardiac tumor necrosis factor-alpha levels in A2BAR-/- compared to WT mice (39.3±5.3 vs 7.5±1.0 pg/mg protein, n=4). Pharmacological studies on human activated PMNs revealed an A2BAR dependent tumor necrosis factor-alpha release. A2BAR signaling on BM-derived cells such as PMNs represents an endogenous cardioprotective mechanism during cardiac IR. Our findings suggest that A2BAR agonist treatment during cardiac IR reduces tumor necrosis factor-alpha release of PMNs, thereby dampening tissue injury.
Publications
- Role of extracellular adenosine in acute lung injury. Physiology (Bethesda). 2009 Oct;24:298-306
Eckle T, Koeppen M, Eltzschig HK
- Selective deletion of the A1 adenosine receptor abolishes heart-rate slowing effects of intravascular adenosine in vivo. PLoS One. 2009 Aug 26;4(8):e6784
Koeppen M, Eckle T, Eltzschig HK
- Interplay of hypoxia and A2B adenosine receptors in tissue protection. Adv Pharmacol. 2011;61:145-86
Koeppen M, Eckle T, Eltzschig HK
- The hypoxia-inflammation link and potential drug targets. Curr Opin Anaesthesiol. 2011 Aug;24(4):363-9
Koeppen M, Eckle T, Eltzschig HK
- Use of a hanging weight system for coronary artery occlusion in mice. J Vis Exp. 2011 Apr 19;(50)
Eckle T, Koeppen M, Eltzschig H
(See online at https://doi.org/10.3791/2526) - Adora2b signaling on bone marrow derived cells dampens myocardial ischemia-reperfusion injury. Anesthesiology, 2012 Apr 23 (epub ahead of print)
Koeppen M, Harter PN, Bonney S, Bonney M, Reithel S, Zachskorn C, Mittelbronn M, Eckle T
(See online at https://doi.org/10.1097/ALN.0b013e318255793c) - Myocardial Ischemia Reperfusion Injury: From Basic Science to Clinical Bedside. Semin Cardiothorac Vasc Anesth. 2012 Feb 23. Epub
Frank A, Bonney M, Bonney S, Weitzel L, Koeppen M, Eckle T
- Transesophageal echocardiography in the diagnosis of acute pericardial tamponade during hiatal hernia repair. J Cardiothorac Vasc Anesth. 2014 Feb;28(1):112-4
Koeppen M, Gravlee GP, Nasrallah F, Eckle T
(See online at https://doi.org/10.1053/j.jvca.2012.09.015)
