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Projekt Druckansicht

Netrin/A2B Adenosin induzierte Cardioprotektion in ischämischer Präkondtionierung

Fachliche Zuordnung Anästhesiologie
Förderung Förderung von 2010 bis 2012
Projektkennung Deutsche Forschungsgemeinschaft (DFG) - Projektnummer 177863205
 
Erstellungsjahr 2014

Zusammenfassung der Projektergebnisse

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.

Projektbezogene Publikationen (Auswahl)

 
 

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