Division of Cardiovascular Medicine, BHF Centre of Research Excellence, Radcliffe Department of Medicine, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DU, UK.
Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK.
Cardiovasc Res. 2018 Aug 1;114(10):1385-1399. doi: 10.1093/cvr/cvy078.
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.
Hyperlipidemic mice deficient in Gch1 in endothelial cells and leucocytes were generated by crossing Gch1fl/flTie2cre 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 Gch1fl/flTie2CreApoE-/- mice resulted in significantly decreased circulating BH4 levels, increased atherosclerosis burden and increased plaque macrophage content. Gch1fl/flTie2CreApoE-/- 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.
Both endothelial cell and macrophage BH4 play important roles in the regulation of NOS function and cellular redox signalling in atherosclerosis.
GTP 环水解酶 I 催化四氢生物蝶呤 (BH4) 合成的第一步和限速反应，BH4 是一氧化氮合酶 (NOS) 的必需辅助因子。eNOS 和 iNOS 都与动脉粥样硬化的进展有关，eNOS 和 iNOS 敲除小鼠的作用相反。然而，BH4 调节 eNOS 和 iNOS 功能的病理生理需求，以及 BH4 缺失对动脉粥样硬化进展的影响尚不清楚。
通过将 Gch1fl/flTie2cre 小鼠与 ApoE-/- 小鼠杂交，生成内皮细胞和白细胞中缺乏 Gch1 的高脂血症小鼠。内皮细胞和髓样细胞中 Gch1 和 BH4 的缺乏与血压轻度升高有关。在 Gch1fl/flTie2CreApoE-/- 小鼠中进行 6 周高脂肪喂养导致循环 BH4 水平显著降低、动脉粥样硬化负担增加和斑块巨噬细胞含量增加。Gch1fl/flTie2CreApoE-/- 小鼠表现出内皮细胞功能障碍的特征，主动脉 VCAM-1 表达增加，内皮细胞依赖性血管舒张减少。此外，促炎巨噬细胞中 BH4 的缺失导致泡沫细胞形成增加和细胞内氧化还原信号改变，抗氧化基因表达减少，活性氧增加。骨髓嵌合体显示，内皮细胞和白细胞中 Gch1 的缺失是加速动脉粥样硬化所必需的。
内皮细胞和巨噬细胞 BH4 都在调节动脉粥样硬化中 NOS 功能和细胞内氧化还原信号中发挥重要作用。
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