Increased activity of vascular adenosine deaminase in atherosclerosis and therapeutic potential of its inhibition
Increased activity of vascular adenosine deaminase in atherosclerosis and therapeutic potential of its inhibition
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DOI：
10.1093/cvr/cvw203
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发表时间：
2016-11-01
影响因子：
10.8
通讯作者：
Smolenski, Ryszard T.
中科院分区：
文献类型：
--
作者：
Kutryb-Zajac, Barbara;Mateuszuk, Lukasz;Smolenski, Ryszard T.
由膜结合胞外酶形成或降解的细胞外核苷酸和腺苷可以通过调节炎症和血栓形成来影响动脉粥样硬化。本研究旨在评估血管壁表面将细胞外三磷酸腺苷转化为磷酸腺嘌呤二核苷酸、单磷酸腺苷、腺苷和肌苷的胞外酶与实验和临床动脉粥样硬化的严重程度或进展之间的关系。此外，我们还测试了抑制腺苷脱氨酶是否会阻止实验性动脉粥样硬化的发展。在载脂蛋白E-/-低密度脂蛋白受体（ApoE-/-LDLR-/-）的主动脉中测量了外核苷三磷酸二磷酸水解酶1、外切5'-核苷酸酶和外切腺苷脱氨酶（eADA）的血管活性。和野生型小鼠以及人类主动脉。通过油红 O 和 Orcein Martius 猩红蓝染色和巨噬细胞的血管积聚对整个主动脉、主动脉根部和头臂动脉中的斑块进行分析。通过免疫荧光分析胞外酶的细胞位置。通过对 ApoE-/-LDLR-/- 小鼠进行为期 2 个月的脱氧考福霉素治疗，研究了 eADA 抑制对动脉粥样硬化进展的影响。与野生型小鼠相比，ApoE-/-LDLR-/-小鼠的血管eADA活性在1个月时就显着增加，并且随着动脉粥样硬化的发展而进展，在10个月时达到10倍的差异。 eADA 的活性与人类主动脉的动脉粥样硬化变化相关。动脉粥样硬化血管中的高丰度 eADA 源自活化的内皮细胞和巨噬细胞。在 ApoE-/-LDLR-/- 小鼠中，外核苷三磷酸二磷酸水解酶 1 活性没有变化，而外核苷 5'-核苷酸酶中度降低。脱氧考福霉素治疗可减弱 ApoE-/-LDLR-/- 小鼠主动脉根部和头臂动脉斑块的形成，抑制血管炎症并改善内皮功能。这项研究强调了动脉粥样硬化血管中细胞外核苷酸和腺苷代谢在实验和临床环境中的重要性。 eADA 活性的增加标志着动脉粥样硬化的早期阶段，有助于其进展，并可能成为新的治疗靶点。
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.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.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.