The adenosine A 2A 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 Hofmann, John P. Headrick, R. Ray Morrison

Research output: Contribution to journalArticle

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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 A 2A adenosine receptor (A 2A AR) 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 A 2A ARs (A 2A AR 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 A 2A ARs increased LPS-provoked cTnI release at 24 h by 3-fold without additional demise of contraction function. Importantly, A 2A AR deletion per se emulated detrimental effects of LPS on coronary function, and LPS was without effect in coronary vessels lacking A 2A ARs. Effects of A 2A AR KO were independent of major shifts in circulating C-reactive protein (CRP) and haptoglobin. Cytokine responses were largely insensitive to A 2A AR deletion; substantial LPS-induced elevations (up to 100-fold) in IFN-γ and IL-10 were unaltered in A 2A AR 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 2A AR KO (IL-2 reduced, IL-5 increased). Data demonstrate that in the context of LPS-triggered cardiac and coronary injury, A 2A AR activity protects myocardial viability without modifying contractile dysfunction, and selectively modulates cytokine (IL-2, IL-5) release. A 2A ARs also appear to be targeted by LPS in the coronary vasculature. Conclusions: These experimental data suggest that preservation of A 2A AR functionality might provide therapeutic benefit in human sepsis.

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

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Adenosine A2A Receptors
Endotoxemia
Lipopolysaccharides
Interleukin-5
Interleukin-2
Troponin I
Wounds and Injuries
Sepsis
Cytokines
Ventricular Dysfunction
Haptoglobins
Interleukin-4
Interleukin-10
C-Reactive Protein
Disease Progression
Coronary Vessels
Inflammation

All Science Journal Classification (ASJC) codes

  • Cardiology and Cardiovascular Medicine

Cite this

Reichelt, M. E., Ashton, K. J., Tan, X. L., Mustafa, S. J., Ledent, C., Delbridge, L. M. D., ... Morrison, R. R. (2013). The adenosine A 2A 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

The adenosine A 2A receptor - Myocardial protectant and coronary target in endotoxemia . / Reichelt, Melissa E.; Ashton, Kevin J.; Tan, Xing Lin; Mustafa, S. Jamal; Ledent, Catherine; Delbridge, Lea M.D.; Hofmann, Polly; Headrick, John P.; Morrison, R. Ray.

In: International Journal of Cardiology, Vol. 166, No. 3, 01.07.2013, p. 672-680.

Research output: Contribution to journalArticle

Reichelt, ME, Ashton, KJ, Tan, XL, Mustafa, SJ, Ledent, C, Delbridge, LMD, Hofmann, P, Headrick, JP & Morrison, RR 2013, ' The adenosine A 2A receptor - Myocardial protectant and coronary target in endotoxemia ', International Journal of Cardiology, vol. 166, no. 3, pp. 672-680. https://doi.org/10.1016/j.ijcard.2011.11.075
Reichelt, Melissa E. ; Ashton, Kevin J. ; Tan, Xing Lin ; Mustafa, S. Jamal ; Ledent, Catherine ; Delbridge, Lea M.D. ; Hofmann, Polly ; Headrick, John P. ; Morrison, R. Ray. / The adenosine A 2A receptor - Myocardial protectant and coronary target in endotoxemia In: International Journal of Cardiology. 2013 ; Vol. 166, No. 3. pp. 672-680.
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