Endothelium-specific sepiapterin reductase deficiency in DOCA-salt hypertension

Ji Youn Youn, Ting Wang, John Blair, Karine M. Laude, Jeong Ho Oak, Louise A. McCann, David G. Harrison, Hua Cai

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20 Scopus citations


The endothelial nitric oxide synthase (eNOS) requires tetrahydrobiopterin (H 4B) as a cofactor and, in its absence, produces superoxide (O 2 -) rather than nitric oxide (NO), a condition referred to as eNOS uncoupling. DOCA-salt-induced hypertension is associated with H 4B oxidation and uncoupling of eNOS. The present study investigated whether administration of sepiapterin or H 4B recouples eNOS in DOCA-salt hypertension. Bioavailable NO detected by electron spin resonance was markedly reduced in aortas of DOCA-salt hypertensive mice. Preincubation with sepiapterin (10 μmol/l for 30 min) failed to improve NO bioavailability 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 H 4B. Indeed, a decreased SPR expression was observed in aortic endothelial cells, but not in endothelium-denuded aortic remains, implicating an endothelium-specific SPR deficiency. Administration of hypertensive aortas with H 4B (10 μmol/l, 30 min) partially restored vascular NO production. Combined administration of H 4B and the NADPH oxidase inhibitor apocynin (100 μmol/l, 30 min) fully restored NO bioavailability while reducing O 2 - production. In angiotensin II-induced hypertension, however, aortic endothelial SPR expression was not affected. In summary, administration of sepiapterin is not effective in recoupling eNOS in DOCA-salt hypertension, due to an endothelium-specific loss in SPR, whereas coadministration of H 4B and apocynin is highly efficient in recoupling eNOS. This is consistent with our previous observations that in angiotensin II hypertension, endothelial deficiency in dihydro-folate reductase is alternatively responsible for uncoupling of eNOS. Taken together, these data indicate that strategies specifically targeting at different H 4B metabolic enzymes might be necessary in restoring eNOS function in different types of hypertension.

Original languageEnglish (US)
Pages (from-to)H2243-H2249
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Issue number11
StatePublished - Jun 1 2012


  • Deoxycorticosterone acetate
  • Endothelial nitric oxide synthase uncoupling
  • Nitric oxide
  • Sepiapterin reductase
  • Superoxide
  • Tetrahydrobiopterin
  • Vascular reduced nicotinamide adenine dinucleotide phosphatase

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)


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