doi: 10.1161/CIRCRESAHA.107.162503
© 2007 American Heart Association, Inc.
Editorials |
Endothelial Cell Tetrahydrobiopterin
Going With the Flow
From the Department of Cardiovascular Medicine, University of Oxford, UK.
Correspondence to Prof Keith M. Channon, Department of Cardiovascular Medicine, John Radcliffe Hospital, Oxford, OX3 9DU, UK. E-mail keith.channon@cardiov.ox.ac.uk
See related article, pages 830–838
Key Words: blood flow • nitric oxide • shear stress
An extract of the first 250 words of the full text is provided, because this article has no abstract. |
The predilection of atherosclerosis for specific locations in the vasculature strongly suggests that the response of the arterial wall to alterations in blood flow is an important factor in vascular disease pathogenesis. Turbulent rather than laminar blood flow reduces shear stress and leads to endothelial cell dysfunction.1 Better understanding of the mechanisms linking laminar shear stress to endothelial cell homeostasis would improve our knowledge of the pathogenesis of atherosclerosis and may provide new therapeutic targets to combat vascular disease.
One major effect of laminar shear stress on endothelial cells is the increased production of nitric oxide (NO), through increased expression of endothelial nitric oxide synthase (eNOS) and by eNOS activation through phosphorylation.2 However, upregulation of eNOS protein alone can have paradoxical deleterious effects on vascular disease pathogenesis.3 In particular, eNOS activity is critically dependent on the cofactor tetrahydrobiopterin (BH4); in the absence of BH4 the eNOS enzyme becomes uncoupled, producing superoxide rather than NO.4,5 Indeed, recent studies in models of atherosclerosis, diabetes, or hypertension indicate that loss of BH4 is an important contributor to endothelial dysfunction.6 Restoration or augmentation of BH4, either pharmacologically or by increasing endothelial cell BH4 biosynthesis, improves NO-mediated endothelial function, with salutary effects on vascular disease pathogenesis.3,7,8 However, the mechanisms that regulate endogenous BH4 levels in the endothelium remain unclear.
In this issue of Circulation Research, Widder and colleagues describe important new mechanisms that link laminar shear stress with increased BH4 levels in human endothelial cells.9 They elegantly reveal how endothelial cell BH4 biosynthesis is
Related Article:
Circ. Res. 2007 101: 830-838.