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

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.

• Authors: Yiming Xu, Yong Wang, Siyuan Yan, Qiuhua Yang, Yaqi Zhou, Xianqiu Zeng, Zhiping Liu, Xiaofei An, Haroldo A Toque, Zheng Dong, Xuejun Jiang, David J Fulton, Neal L Weintraub, Qinkai Li, Zsolt Bagi, Mei Hong, Detlev Boison, Chaodong Wu, Yuqing Huo
• Journal: Nature communications (Nat Commun) Vol. 8 Issue 1 Pg. 943 (10 16 2017) ISSN: 2041-1723 [Electronic] England
• PMID: 29038540 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Adenosine Kinase
• Adenosylhomocysteinase
• Adenosine

Topics

• Adenosine (immunology)
• Adenosine Kinase (genetics, immunology)
• Adenosylhomocysteinase (metabolism)
• Animals
• Atherosclerosis (genetics, immunology)
• Blood Vessels (immunology)
• Cerebral Cortex (blood supply)
• Endothelial Cells (immunology)
• Epigenesis, Genetic (genetics, immunology)
• Gene Expression Regulation (immunology)
• Gene Knockdown Techniques
• Inflammation (genetics, immunology)
• Mice
• Mice, Knockout, ApoE
• Reperfusion Injury (genetics, immunology)