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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.
Highlights
The molecular mechanisms underlying vascular inflammation and associated inflammatory vascular diseases are not well defined
We found that Tumor necrosis factor (TNF)-α treatment did not affect the mRNA level but upregulated the protein level of adenosine kinase (ADK) (Fig. 1a)
Consistent with the enhanced level of adenosine-metabolizing enzyme, intracellular adenosine levels significantly decreased in human umbilical vein endothelial cells (HUVECs) exposed to TNF-α for 6 and 12 h (Fig. 1b)
Summary
The molecular mechanisms underlying vascular inflammation and associated inflammatory vascular diseases are not well defined. 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. 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. Vascular Biology Center, Department of Cellular Biology and Anatomy, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA. Our study showed that ADK inactivation elevates intracellular adenosine and inhibits inflammatory response via decreasing the pro-inflammatory stimuli-induced hypermethylation of histone H3 at lysine 4 (H3K4), indicating the therapeutic potential of targeting ADK for inflammatory vascular disorders
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