期刊
CARDIOVASCULAR RESEARCH
卷 114, 期 10, 页码 1385-1399出版社
OXFORD UNIV PRESS
DOI: 10.1093/cvr/cvy078
关键词
GCH; Tetrahydrobiopterin; Atherosclerosis; Macrophages; Endothelial cells
资金
- British Heart Foundation [RG/12/5/29576, CH/16/1/32013]
- Oxford British Heart Foundation Centre of Research Excellence [RE/13/1/30181]
- Wellcome Trust [090532/Z/09/Z]
- National Institute for Health Research (NIHR) Oxford Biomedical Research Centre
Aims GTP cyclohydrolase I catalyses the first and rate-limiting reaction in the synthesis of tetrahydrobiopterin (BH4), an essential cofactor for nitric oxide synthases (NOS). Both eNOS and iNOS have been implicated in the progression of atherosclerosis, with opposing effects in eNOS and iNOS knockout mice. However, the pathophysiologic requirement for BH4 in regulating both eNOS and iNOS function, and the effects of loss of BH4 on the progression of atherosclerosis remains unknown. Methods and results Hyperlipidemic mice deficient in Gch1 in endothelial cells and leucocytes were generated by crossing Gch1(fl/fl) Tie2cre mice with ApoE(-/-) mice. Deficiency of Gch1 and BH4 in endothelial cells and myeloid cells was associated with mildly increased blood pressure. High fat feeding for 6 weeks in Gch1(fl/fl) Tie2CreApoE(-/-) mice resulted in significantly decreased circulating BH4 levels, increased atherosclerosis burden and increased plaque macrophage content. Gch1(fl/fl) Tie2CreApoE(-/-) mice showed hallmarks of endothelial cell dysfunction, with increased aortic VCAM-1 expression and decreased endothelial cell dependent vasodilation. Furthermore, loss of BH4 from pro-inflammatory macrophages resulted in increased foam cell formation and altered cellular redox signalling, with decreased expression of antioxidant genes and increased reactive oxygen species. Bone marrow chimeras revealed that loss of Gch1 in both endothelial cells and leucocytes is required to accelerate atherosclerosis. Conclusion Both endothelial cell and macrophage BH4 play important roles in the regulation of NOS function and cellular redox signalling in atherosclerosis.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据