Increased activity of vascular adenosine deaminase in atherosclerosis and therapeutic potential of its inhibition
| Autor: | Barbara Sitek, Marta Toczek, Lukasz Mateuszuk, Barbara Kutryb-Zajac, Romuald Lango, Jan Rogowski, Agnieszka Zakrzewska, Ewa M. Slominska, Agnieszka Jasztal, Ryszard T. Smolenski, Patrycja Jablonska, Magdalena A. Zabielska, Paulina Zukowska, Stefan Chlopicki |
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| Jazyk: | angličtina |
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Adenosine monophosphate Male medicine.medical_specialty Adenosine Apolipoprotein B Endothelium endothelium Physiology Adenosine Deaminase Fluorescent Antibody Technique Inflammation Biology 03 medical and health sciences chemistry.chemical_compound Mice Adenosine deaminase Apolipoproteins E Physiology (medical) Internal medicine medicine Adenosine Deaminase Inhibitors Animals Humans Aorta Cells Cultured Atherosclerosis nucleotides adenosine deaminase Mice Inbred C57BL Disease Models Animal 030104 developmental biology Endocrinology medicine.anatomical_structure chemistry Receptors LDL adenosine Immunology biology.protein Deoxycoformycin medicine.symptom atherosclerosis Cardiology and Cardiovascular Medicine Adenosine triphosphate Pentostatin medicine.drug |
| Popis: | Aims Extracellular nucleotides and adenosine that are formed or degraded by membrane-bound ecto-enzymes could affect atherosclerosis by regulating the inflammation and thrombosis. This study aimed to evaluate a relation between ecto-enzymes that convert extracellular adenosine triphosphate to adenine dinucleotide phosphate, adenosine monophosphate, adenosine, and inosine on the surface of the vessel wall with the severity or progression of experimental and clinical atherosclerosis. Furthermore, we tested whether the inhibition of adenosine deaminase will block the development of experimental atherosclerosis. 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. |
| Databáze: | OpenAIRE |
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