TY - JOUR
T1 - Regulation of endothelial intracellular adenosine via adenosine kinase epigenetically modulates vascular inflammation
AU - Xu, Yiming
AU - Wang, Yong
AU - Yan, Siyuan
AU - Yang, Qiuhua
AU - Zhou, Yaqi
AU - Zeng, Xianqiu
AU - Liu, Zhiping
AU - An, Xiaofei
AU - Flores Toque, Haroldo Alfredo
AU - Dong, Zheng
AU - Jiang, Xuejun
AU - Fulton, David J
AU - Weintraub, Neal Lee
AU - Li, Qinkai
AU - Bagi, Zsolt
AU - Hong, Mei
AU - Boison, Detlev
AU - Wu, Chaodong
AU - Huo, Yuqing
N1 - Funding Information:
We would like to acknowledge statistical advice from Dr Hongyan Xu (Department of Biostatistics and Epidemiology, Medical College of Georgia, Augusta University). This work was supported by grants from National Key Basic Research Program of China (2012CB910402), National Natural Science Foundation of China (81400826), Guangdong Natural Science Foundation (2014A030312004), the Shenzhen Science and Technology Innovation Committee (20160517084712652, 20160503001803075, JCYJ20140903101709818, JSGG20140717102922014), the Shenzhen Peacock Program (KQCX2015032709315529), American Heart Association (15POST22810024, 16GRNT30510010) and the National Institutes of Health (HL095556, R01DK095862).
Publisher Copyright:
© 2017 The Author(s).
PY - 2017/12/1
Y1 - 2017/12/1
N2 - 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.
AB - 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.
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U2 - 10.1038/s41467-017-00986-7
DO - 10.1038/s41467-017-00986-7
M3 - Article
C2 - 29038540
AN - SCOPUS:85031799054
SN - 2041-1723
VL - 8
JO - Nature communications
JF - Nature communications
IS - 1
M1 - 943
ER -