Tetrahydrobiopterin supplementation reduces atherosclerosis and vascular inflammation in Apolipoprotein E-knockout mice
Résumé
Tetrahydrobiopterin (BH4) supplementation improves endothelial function in models of vascular disease by maintaining endothelial nitric oxide synthase coupling and nitric oxide bioavailability. However, the cellular mechanisms through which enhanced endothelial function leads to reduced atherosclerosis remain unclear. We have used a pharmaceutical BH4 formulation to investigate the effects of BH4 supplementation on atherosclerosis progression in ApoE-KO mice. Single oral dose pharmacokinetic studies revealed rapid BH4 uptake into plasma and organs. Plasma BH4 levels returned to baseline by 8 hours after oral dosing, but remained markedly increased in aorta at 24 hours. Daily oral BH4 supplementation in 8 week old chow-fed ApoE-KO mice for 8 or 12 weeks had no effect on plasma lipids or hemodynamic parameters, but significantly reduced aortic root atherosclerosis, compared with placebo treated animals. BH4 supplementation significantly reduced VCAM-1 RNA levels on aortic endothelial cells, markedly reduced the infiltration of T cells, macrophages and monocytes into plaques and reduced T cell infiltration in the adjacent adventitia, but importantly had no effect on circulating leukocytes. GTP-cyclohydrolase 1 transgenic mice, with a specific increase in endothelial BH4 levels, exhibited a similar reduction in vascular immune cell infiltration compared with BH4 deficient controls, suggesting that BH4 reduces vascular inflammation through endothelial cell signalling. BH4 supplementation reduces vascular immune cell infiltration in atherosclerosis and may therefore be a rational therapeutic approach to reduce the progression of atherosclerosis.
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