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Endothelial deficiency of sepiapterin reductase in hypertension and its impact on sepiapterin as an eNOS‐recoupling agent
Author(s) -
Blair John,
Oak JeongHo,
Harrison David,
Cai Hua “Linda”
Publication year - 2006
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.20.4.a652-b
Subject(s) - enos , medicine , endocrinology , tetrahydrobiopterin , chemistry , endothelial dysfunction , biopterin , endothelium , nitric oxide , nitric oxide synthase
DOCA salt‐induced hypertension is associated with oxidation of tetrahydrobiopterin (H4B) and uncoupling of eNOS. We sought to examine whether administration of H4B precursor sepiapterin restores eNOS function. Bioavailable NO detected by electron spin resonance (ESR) was markedly reduced in aortas of DOCA‐salt hypertensive mice. Pre‐incubation with sepiapterin (10 æmol/L for 30 min) failed to increase NO in hypertensive aortas while it augmented NO production from control vessels, implicating a hypertension‐associated deficiency in sepiapterin reductase (SPR), the rate‐limiting enzyme for sepiapterin conversion to H4B. Indeed, western analysis revealed a decrease in SPR expression in whole aortic homogenates of hypertensive mice. The rabbit anti‐serum for SPR was assessed using antibody clearance, and proved specific and reproducible in detecting SPR monomer of 28 kD in aortic homogenates. Differential western analysis using isolated pure endothelial cells and aortas denuded of endothelium indicated that SPR was only downregulated in the endothelium. Chronic infusion of sepiapterin (10 mg/kg/day) upregulated SPR expression in control mice while had mixed responses in hypertensive mice. In summary, administration of sepiapterin is ineffective in recoupling eNOS in hypertension, likely due to a loss in SPR at baseline and a failure of substrate‐induced upregulation. This may explain the previously reported inconsistency of sepiapterin in modulating endothelium‐dependent vasorelaxation in different models of vascular diseases. This work is supported by American Heart Association and American Diabetes Association Grants 0435189N and 7‐04‐RA‐16, and NIH Grants HL077440 and HL081571 (all to H Cai)