Abstract | AIMS: METHODS AND RESULTS: Vascular activities of ecto- nucleoside triphosphate diphosphohydrolase 1, ecto-5'-nucleotidase, and ecto- adenosine deaminase (eADA) were measured in aortas of apolipoprotein E-/- low density lipoprotein receptor ( ApoE-/-LDLR-/-) and wild-type mice as well as in human aortas. Plaques were analysed in the entire aorta, aortic root, and brachiocephalic artery by Oil-Red O and Orcein Martius Scarlet Blue staining and vascular accumulation of macrophages. The cellular location of ecto- enzymes was analysed by immunofluorescence. The effect of eADA inhibition on atherosclerosis progression was studied by a 2-month deoxycoformycin treatment of ApoE-/-LDLR-/- mice. The vascular eADA activity prominently increased in ApoE-/-LDLR-/- mice when compared with wild type already at the age of 1 month and progressed along atherosclerosis development, reaching a 10-fold difference at 10 months. The activity of eADA correlated with atherosclerotic changes in human aortas. High abundance of eADA in atherosclerotic vessels originated from activated endothelial cells and macrophages. There were no changes in ecto- nucleoside triphosphate diphosphohydrolase 1 activity, whereas ecto-5'-nucleotidase was moderately decreased in ApoE-/-LDLR-/- mice. Deoxycoformycin treatment attenuated plaque development in aortic root and brachiocephalic artery of ApoE-/-LDLR-/- mice, suppressed vascular inflammation and improved endothelial function. CONCLUSIONS: This study highlights the importance of extracellular nucleotides and adenosine metabolism in the atherosclerotic vessel in both experimental and clinical setting. The increased eADA activity marks an early stage of atherosclerosis, contributes to its progression and could represent a novel target for therapy.
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Authors | Barbara Kutryb-Zajac, Lukasz Mateuszuk, Paulina Zukowska, Agnieszka Jasztal, Magdalena A Zabielska, Marta Toczek, Patrycja Jablonska, Agnieszka Zakrzewska, Barbara Sitek, Jan Rogowski, Romuald Lango, Ewa M Slominska, Stefan Chlopicki, Ryszard T Smolenski |
Journal | Cardiovascular research
(Cardiovasc Res)
Vol. 112
Issue 2
Pg. 590-605
(Nov 01 2016)
ISSN: 1755-3245 [Electronic] England |
PMID | 28513806
(Publication Type: Journal Article)
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Copyright | Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2016. For Permissions, please email: [email protected]. |
Chemical References |
- Adenosine Deaminase Inhibitors
- Apolipoproteins E
- Receptors, LDL
- Pentostatin
- Adenosine Deaminase
- Adenosine
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Topics |
- Adenosine
(metabolism)
- Adenosine Deaminase
(metabolism)
- Adenosine Deaminase Inhibitors
(therapeutic use)
- Animals
- Aorta
(enzymology, metabolism)
- Apolipoproteins E
(physiology)
- Atherosclerosis
(drug therapy, metabolism)
- Cells, Cultured
- Disease Models, Animal
- Fluorescent Antibody Technique
- Humans
- Male
- Mice
- Mice, Inbred C57BL
- Pentostatin
(pharmacology)
- Receptors, LDL
(physiology)
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