Journal
CIRCULATION RESEARCH
Volume 118, Issue 6, Pages 944-956Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/CIRCRESAHA.115.307674
Keywords
arteriosclerosis; inflammation; intercellular adhesion molecule-1; methylation; NSun2
Funding
- National Natural Science Foundation of China [91439206, 81370006, 91339114]
- National Basic Research Program of P. R. China [2011CB503904]
- (111 project) from Ministry of Education of P. R. China [B07001]
- British Heart Foundation [RG/14/6/31144] Funding Source: researchfish
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Rationale: Vascular endothelial inflammation, including the expression of intercellular adhesion molecule 1 (ICAM-1), is a key event in vascular diseases. However, the mechanisms underlying the regulation of ICAM-1 are largely unknown. Objective: To investigate the mechanisms on the regulation of ICAM-1 by NOP2/Sun domain family, member 2 (NSun2)-mediated mRNA methylation and the impact of NSun2-ICAM-1 regulatory process in vascular inflammation and allograft arteriosclerosis. Methods and Results: By using in vitro, in cells, and in vivo methylation assays, we showed that the tRNA methyltransferase NSun2 methylated the ICAM-1 mRNA. Methylation by NSun2 promoted the translation of ICAM-1, thereby increasing the adhesion of leukocytes to endothelial cells. Tumor necrosis factor- or homocysteine activated the methyltransferase activity of NSun2 by repressing the phosphorylation of NSun2 by Aurora-B. The levels of ICAM-1 induction and of leukocyte adhesion to vascular endothelium observed with homocysteine treatment in wild-type rats were markedly decreased in NSun2(-/-) rats. In a rat model of aortic allograft, the lack of donor NSun2 impaired the formation of allograft arteriosclerosis. Conclusions: NSun2 upregulates the expression of ICAM-1 by methylating ICAM-1 mRNA. This regulatory process impacts on vascular inflammation and allograft arteriosclerosis.
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