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Acta Physiologica 2009; Volume 195, Supplement 669
The 88th Annual Meeting of The German Physiological Society
3/22/2009-3/25/2009
Giessen, Germany
ACCELERATED ATHEROSCLEROSIS INAPOLIPOPROTEIN E/ECTO-5NUCLEOTIDASE (CD73) DOUBLE-DEFICIENT MICE
Abstract number: O7
Pexa1 A., Buchheiser1 A., Ding1 Z., Romio1 M., Burghoff1 S., Lindecke2 A., Kohrer2 K., Fischer3 J., Schrader1 J.
1Herz- und Kreislaufphysiologie, Heinrich-Heine Universitt Dsseldorf, Dsseldorf
2Biologisch-Medizinisches Forschungszentrum, Heinrich-Heine Universitt Dsseldorf, Dsseldorf
3Molekulare Pharmakologie, Heinrich-Heine Universitt Dsseldorf, Dsseldorf
The aim of this study was to explore the role of CD73-derived adenosine in a model of chronic inflammation by backcrossing CD73-/- mice into the ApoE-/- background. In CD73-/-/ApoE-/- double mutants atherosclerotic lesion formation was increased by 50% in aorta as evidenced by Oil Red O staining and by cholesterol staining in crossections at the aortic sinus. Total serum cholesterol and LDL cholesterol were elevated in both groups - CD73-/-/ApoE-/- double mutants and age-matched ApoE-/- control mice - but there was no difference between the two groups. We found an elevation in the plasma levels of MCP-1 in CD73-/-/ApoE-/- double mutants and age-matched ApoE-/- control mice compared to wild type mice and the CD73-/-/ApoE-/- double deficient mice developed even significantly higher plasma levels compared to ApoE-/- controls. However, the cellular composition (plaque infiltrating macrophages and CD4+ T-cells) and extracellular matrix (collagen, cholesterol and hyaluronic acid) of the plaques did not differ compared to ApoE-/- controls.
Surprisingly, we found significant activity and expression of CD73 in the plaque of ApoE-/- mice in aorta and at the aortic sinus. The expression and activity of CD73, paralleled by the plaque size, increased with age from 6 month to 12 month. CD73 co-localized with foxp3 positive cells (Treg), macrophages and cells of mesenchymal origin in the adventitia and with macrophages and cells of mesenchymal origin in the plaque area. Foxp3+ cells are present in the plaque, but in contrast to the adventitia, there is no co-localization of foxp3+ cells with CD73. In order to gain mechanistic insight, we performed a genome-wide microarray analysis of the aorta of CD73-/- mice. Among other genes, of which many were involved in WNT and NFkB signalling pathways, it revealed up regulation of endothelin-1 mRNA. Endothelin-1 is described to be involved in atherogenesis. We measured the plasma levels of endothelin-1 and found a significant elevation of plasma endothelin-1 in CD73-/- mice and CD73-/-/ApoE-/- double mutants compared to the respective controls.
Taken together, lack of CD73-mediated adenosine formation promotes atherogenesis which is likely to involve activation of the endothelium, resident macrophages and T cells. The elevated plasma endothelin-1 may have added the atherosclerotic phenotype of CD73-/-/ApoE-/- mice.
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Acta Physiologica 2009; Volume 195, Supplement 669 :O7