Endothelium-specific sepiapterin reductase deficiency in DOCA-salt hypertension Article

Youn, JY, Wang, T, Blair, J et al. (2012). Endothelium-specific sepiapterin reductase deficiency in DOCA-salt hypertension . AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY, 302(11), 10.1152/ajpheart.00835.2011

cited authors

  • Youn, JY; Wang, T; Blair, J; Laude, KM; Oak, JH; McCann, LA; Harrison, DG; Cai, H



  • 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. © 2012 the American Physiological Society.

publication date

  • June 1, 2012

Digital Object Identifier (DOI)


  • 302


  • 11