Complete deletion of Cd39 is atheroprotective in apolipoprotein E-deficient mice.

Abstract

Cd39 scavenges extracellular ATP and ADP, ultimately generating adenosine, a nucleoside, which has anti-inflammatory effects in the vasculature. We have evaluated the role of Cd39 in the development of atherosclerosis in hyperlipidemic mice. ApoE KO (Cd39+/+/ApoE-/-) and Cd39/ApoE double KO (DKO) (Cd39-/-/ApoE-/-) mice were maintained on chow or Western diet for up to 20 weeks before evaluation of atherosclerotic lesions. We found that DKO mice exhibited significantly fewer atherosclerotic lesions than ApoE KO mice, irrespective of diet. Analyses of plaque composition revealed diminished foam cells in the fatty streaks and smaller necrotic cores in advanced lesions of DKO mice, when compared with those in ApoE KO mice. This atheroprotective phenotype was associated with impaired platelet reactivity to ADP in vitro and prolonged platelet survival, suggesting decreased platelet activation in vivo. Further studies with either genetic deletion or pharmacological inhibition of Cd39 in macrophages revealed increased cholesterol efflux mediated via ABCA1 to ApoA1. This phenomenon was associated with elevated plasma HDL levels in DKO mice. Our findings indicate that complete deletion of Cd39 paradoxically attenuates development of atherosclerosis in hyperlipidemic mice. We propose that this phenotype occurs, at least in part, from diminished platelet activation, increased plasma HDL levels, and enhanced cholesterol efflux and indicates the complexity of purinergic signaling in atherosclerosis.

• Authors: Marco De Giorgi, Keiichi Enjyoji, Gordon Jiang, Eva Csizmadia, Shuji Mitsuhashi, Richard J Gumina, Ryszard T Smolenski, Simon C Robson
• Journal: Journal of lipid research (J Lipid Res) Vol. 58 Issue 7 Pg. 1292-1305 (07 2017) ISSN: 1539-7262 [Electronic] United States
• PMID: 28487312 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, N.I.H., Extramural)
• Copyright: Copyright © 2017 by the American Society for Biochemistry and Molecular Biology, Inc.

Chemical References

• Antigens, CD
• Apolipoproteins E
• Cholesterol
• Apyrase
• CD39 antigen

Topics

• Animals
• Antigens, CD (genetics)
• Apolipoproteins E (deficiency)
• Apyrase (deficiency, genetics)
• Atherosclerosis (genetics, metabolism, pathology, physiopathology)
• Biological Transport (genetics)
• Cell Movement (genetics)
• Cell Proliferation (genetics)
• Cholesterol (metabolism)
• Gene Knockout Techniques
• Macrophages (metabolism)
• Male
• Mice
• Muscle, Smooth, Vascular (pathology)
• Necrosis (genetics)
• Phenotype
• Platelet Activation (genetics)