Infarct-Sparing Effect of Adenosine A2B Receptor Agonist Is Primarily Due to Its Action on Splenic Leukocytes Via a PI3K/Akt/IL-10 Pathway.

Abstract

BACKGROUND:

Adenosine A2B receptor (A2BAR) agonist reduces myocardial reperfusion injury by acting on inflammatory cells. Recently, a cardiosplenic axis was shown to mediate the myocardial postischemic reperfusion injury. This study aimed to explore whether the infarct-squaring effect of A2BAR agonist was primarily due to its action on splenic leukocytes.

METHODS:

C57BL6 (wild type [WT]) mice underwent 40 min of left coronary artery occlusion followed by 60 min of reperfusion. A2BAR knockout (KO) and interleukin (IL)-10KO mice served as donors for splenic leukocytes. Acute splenectomy was performed 30 min before ischemia. The acute splenic leukocyte adoptive transfer was performed by injecting 5 × 106 live splenic leukocytes into splenectomized mice. BAY 60-6583, an A2BAR agonist, was injected by i.v. 15 min before ischemia. The infarct size (IS) was determined using 2,3,5-triphenyltetrazolium chloride and Phthalo blue staining. The expression of p-Akt and IL-10 was estimated by Western blotting. Immunofluorescence staining assessed the localization of IL-10 expression.

RESULTS:

BAY 60-6583 reduced the myocardial IS in intact mice but failed to reduce the same in splenectomized mice, which had a smaller IS than intact mice. BAY 60-6583 reduced the IS in splenectomized mice with the acute transfer of WT splenic leukocytes; however, it did not protect the heart of splenectomized mice with the acute transfer of A2BRKO splenic leukocytes. Furthermore, BAY 60-6583 increased the levels of p-Akt and IL-10 in the WT spleen. Moreover, it did not exert any protective effect in IL-10KO mice.

CONCLUSIONS:

A2BAR activation before ischemia stimulated the IL-10 production in splenic leukocytes via a PI3K/Akt pathway, thereby exerting anti-inflammatory effects that limited the myocardial reperfusion injury.

• Authors: Yingying Ni, Degang Liang, Yikui Tian, Irving L Kron, Brent A French, Zequan Yang
• Journal: The Journal of surgical research (J Surg Res) Vol. 232 Pg. 442-449 (12 2018) ISSN: 1095-8673 [Electronic] United States
• PMID: 30463755 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2018 Elsevier Inc. All rights reserved.

Chemical References

• Adenosine A2 Receptor Agonists
• Aminopyridines
• BAY 60-6583
• Interleukin-10
• Phosphatidylinositol 3-Kinases
• Proto-Oncogene Proteins c-akt

Topics

• Adenosine A2 Receptor Agonists (therapeutic use)
• Aminopyridines (therapeutic use)
• Animals
• Interleukin-10 (physiology)
• Leukocytes (drug effects)
• Mice
• Mice, Inbred C57BL
• Myocardial Infarction (prevention & control)
• Myocardial Reperfusion Injury (prevention & control)
• Phosphatidylinositol 3-Kinases (physiology)
• Proto-Oncogene Proteins c-akt (physiology)
• Signal Transduction (physiology)
• Spleen (drug effects, physiology)