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Nat Commun. 2017 Oct 16;8(1):943. doi: 10.1038/s41467-017-00986-7.

Regulation of endothelial intracellular adenosine via adenosine kinase epigenetically modulates vascular inflammation.

Xu Y1,2, Wang Y3,4, Yan S3,5, Yang Q3,6, Zhou Y3,6, Zeng X3,6, Liu Z3,6, An X3,7, Toque HA8, Dong Z9, Jiang X5, Fulton DJ3, Weintraub NL3, Li Q6, Bagi Z3, Hong M6, Boison D10, Wu C11, Huo Y12,13,14.

Author information

1
Vascular Biology Center, Department of Cellular Biology and Anatomy, Medical College of Georgia, Augusta University, Augusta, GA, 30912, USA. xuyiming0807@gmail.com.
2
School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, 511436, China. xuyiming0807@gmail.com.
3
Vascular Biology Center, Department of Cellular Biology and Anatomy, Medical College of Georgia, Augusta University, Augusta, GA, 30912, USA.
4
College of Basic Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, 610075, China.
5
State Key Laboratory of Mycology, Institute of Microbiology, Chinese Academy of Science, Beijing, 100101, China.
6
Drug Discovery Center, Key Laboratory of Chemical Genomics, Peking University Shenzhen Graduate School, Shenzhen, 518055, China.
7
Department of Endocrinology, Jiangsu Province Hospital of Chinese Medicine, Nanjing, 210029, China.
8
Department of Pharmacology and Toxicology, Augusta University, Augusta, GA, 30912, USA.
9
Department of Cellular Biology and Anatomy, Medical College of Georgia, Augusta University, Augusta, GA, 30912, USA.
10
Robert S. Dow Neurobiology Laboratories, Legacy Research Institute, Portland, OR, 97232, USA.
11
Department of Nutrition and Food Science, Texas A&M University, College Station, TX, 77840, USA.
12
Vascular Biology Center, Department of Cellular Biology and Anatomy, Medical College of Georgia, Augusta University, Augusta, GA, 30912, USA. yhuo@augusta.edu.
13
Drug Discovery Center, Key Laboratory of Chemical Genomics, Peking University Shenzhen Graduate School, Shenzhen, 518055, China. yhuo@augusta.edu.
14
Department of Cellular Biology and Anatomy, Medical College of Georgia, Augusta University, Augusta, GA, 30912, USA. yhuo@augusta.edu.

Abstract

The molecular mechanisms underlying vascular inflammation and associated inflammatory vascular diseases are not well defined. Here we show that endothelial intracellular adenosine and its key regulator adenosine kinase (ADK) play important roles in vascular inflammation. Pro-inflammatory stimuli lead to endothelial inflammation by increasing endothelial ADK expression, reducing the level of intracellular adenosine in endothelial cells, and activating the transmethylation pathway through increasing the association of ADK with S-adenosylhomocysteine (SAH) hydrolase (SAHH). Increasing intracellular adenosine by genetic ADK knockdown or exogenous adenosine reduces activation of the transmethylation pathway and attenuates the endothelial inflammatory response. In addition, loss of endothelial ADK in mice leads to reduced atherosclerosis and affords protection against ischemia/reperfusion injury of the cerebral cortex. Taken together, these results demonstrate that intracellular adenosine, which is controlled by the key molecular regulator ADK, influences endothelial inflammation and vascular inflammatory diseases.The molecular mechanisms underlying vascular inflammation are unclear. Here the authors show that pro-inflammatory stimuli lead to endothelial inflammation by increasing adenosine kinase expression, and that its knockdown in endothelial cells inhibits atherosclerosis and cerebral ischemic injury in mice.

PMID:
29038540
PMCID:
PMC5643397
DOI:
10.1038/s41467-017-00986-7
[Indexed for MEDLINE]
Free PMC Article

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