The adenosine A2A receptor - Myocardial protectant and coronary target in endotoxemia

Melissa E. Reichelt*, Kevin J. Ashton, Xing Lin Tan, S. Jamal Mustafa, Catherine Ledent, Lea M D Delbridge, Polly A. Hofmann, John P. Headrick, R. Ray Morrison

*Corresponding author for this work

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Abstract

Background: Cardiac injury and dysfunction are contributors to disease progression and mortality in sepsis. This study evaluated the cardiovascular role of intrinsic A2A adenosine receptor (A2AAR) activity during lipopolysaccharide (LPS)-induced inflammation. Methods: We assessed the impact of 24 h of LPS challenge (20 mg/kg, IP) on cardiac injury, coronary function and inflammatory mediator levels in Wild-Type (WT) mice and mice lacking functional A2AARs (A2AAR KO). Results: Cardiac injury was evident in LPS-treated WTs, with ∼7-fold elevation in serum cardiac troponin I (cTnI), and significant ventricular and coronary dysfunction. Absence of A2AARs increased LPS-provoked cTnI release at 24 h by 3-fold without additional demise of contraction function. Importantly, A 2AAR deletion per se emulated detrimental effects of LPS on coronary function, and LPS was without effect in coronary vessels lacking A 2AARs. Effects of A2AAR KO were independent of major shifts in circulating C-reactive protein (CRP) and haptoglobin. Cytokine responses were largely insensitive to A2AAR deletion; substantial LPS-induced elevations (up to 100-fold) in IFN-γ and IL-10 were unaltered in A2AAR KO mice, as were levels of IL-4 and TNF-α. However, late elevations in IL-2 and IL-5 were differentially modulated by A 2AAR KO (IL-2 reduced, IL-5 increased). Data demonstrate that in the context of LPS-triggered cardiac and coronary injury, A2AAR activity protects myocardial viability without modifying contractile dysfunction, and selectively modulates cytokine (IL-2, IL-5) release. A2AARs also appear to be targeted by LPS in the coronary vasculature. Conclusions: These experimental data suggest that preservation of A2AAR functionality might provide therapeutic benefit in human sepsis.

Original languageEnglish
Pages (from-to)672-680
Number of pages9
JournalInternational Journal of Cardiology
Volume166
Issue number3
DOIs
Publication statusPublished - 1 Jul 2013

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Reichelt, M. E., Ashton, K. J., Tan, X. L., Mustafa, S. J., Ledent, C., Delbridge, L. M. D., ... Morrison, R. R. (2013). The adenosine A2A receptor - Myocardial protectant and coronary target in endotoxemia. International Journal of Cardiology, 166(3), 672-680. https://doi.org/10.1016/j.ijcard.2011.11.075