Role of A2B adenosine receptors in regulation of paracrine functions of stem cell antigen 1-positive cardiac stromal cells.

Ryzhov S, Goldstein AE, Novitskiy SV, Blackburn MR, Biaggioni I, Feoktistov I
J Pharmacol Exp Ther. 2012 341 (3): 764-74

PMID: 22431204 · PMCID: PMC3362889 · DOI:10.1124/jpet.111.190835

The existence of multipotent cardiac stromal cells expressing stem cell antigen (Sca)-1 has been reported, and their proangiogenic properties have been demonstrated in myocardial infarction models. In this study, we tested the hypothesis that stimulation of adenosine receptors on cardiac Sca-1(+) cells up-regulates their secretion of proangiogenic factors. We found that Sca-1 is expressed in subsets of mouse cardiac stromal CD31(-) and endothelial CD31(+) cells. The population of Sca-1(+)CD31(+) endothelial cells was significantly reduced, whereas the population of Sca-1(+)CD31(-) stromal cells was increased 1 week after myocardial infarction, indicating their relative functional importance in this pathophysiological process. An increase in adenosine levels in adenosine deaminase-deficient mice in vivo significantly augmented vascular endothelial growth factor (VEGF) production in cardiac Sca-1(+)CD31(-) stromal cells but not in Sca-1(+)CD31(+) endothelial cells. We found that mouse cardiac Sca-1(+)CD31(-) stromal cells predominantly express mRNA encoding A(2B) adenosine receptors. Stimulation of adenosine receptors significantly increased interleukin (IL)-6, CXCL1 (a mouse ortholog of human IL-8), and VEGF release from these cells. Using conditionally immortalized Sca-1(+)CD31(-) stromal cells obtained from wild-type and A(2B) receptor knockout mouse hearts, we demonstrated that A(2B) receptors are essential for adenosine-dependent up-regulation of their paracrine functions. We found that the human heart also harbors a population of stromal cells similar to the mouse cardiac Sca-1(+)CD31(-) stromal cells that increase release of IL-6, IL-8, and VEGF in response to A(2B) receptor stimulation. Thus, our study identified A(2B) adenosine receptors on cardiac stromal cells as potential targets for up-regulation of proangiogenic factors in the ischemic heart.

MeSH Terms (26)

Adenosine Adenosine Deaminase Agammaglobulinemia Animals Antigens, Ly Cells, Cultured Chemokine CXCL1 Female Interleukin-6 Male Membrane Proteins Mesenchymal Stem Cells Mice Mice, Inbred C57BL Mice, Knockout Mice, Transgenic Myocardial Infarction Myocardium Paracrine Communication Platelet Endothelial Cell Adhesion Molecule-1 Receptor, Adenosine A2B RNA, Messenger Severe Combined Immunodeficiency Stem Cells Up-Regulation Vascular Endothelial Growth Factor A

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