title: Endothelium-specific sepiapterin reductase deficiency in DOCA-salt hypertension.
abstract: The endothelial nitric oxide synthase (eNOS) requires tetrahydrobiopterin (H(4)B) 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(4)B oxidation and uncoupling of eNOS. The present study investigated whether administration of sepiapterin or H(4)B 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(4)B. 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(4)B (10 μmol/l, 30 min) partially restored vascular NO(·) production. Combined administration of H(4)B 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(4)B and apocynin is highly efficient in recoupling eNOS. This is consistent with our previous observations that in angiotensin II hypertension, endothelial deficiency in dihydrofolate reductase is alternatively responsible for uncoupling of eNOS. Taken together, these data indicate that strategies specifically targeting at different H(4)B metabolic enzymes might be necessary in restoring eNOS function in different types of hypertension.
authors.affiliation: Division of Molecular Medicine, Cardiovascular Research Laboratories, Department of Anesthesiology, David Geffen School of Medicine at University of California Los Angeles, 90095, USA.
authors.forename: Ji Youn
authors.initials: JY
authors.lastname: Youn
authors.forename: Ting
authors.initials: T
authors.lastname: Wang
authors.forename: John
authors.initials: J
authors.lastname: Blair
authors.forename: Karine M
authors.initials: KM
authors.lastname: Laude
authors.forename: Jeong-Ho
authors.initials: JH
authors.lastname: Oak
authors.forename: Louise A
authors.initials: LA
authors.lastname: McCann
authors.forename: David G
authors.initials: DG
authors.lastname: Harrison
authors.forename: Hua
authors.initials: H
authors.lastname: Cai
mesh_terms: D000098:Acetophenones / Q000494:pharmacology; D000429:Alcohol Oxidoreductases / Q000172:deficiency*; D000818:Animals; D001011:Aorta / Q000378:metabolism*; D001708:Biopterins / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology; D001794:Blood Pressure; D003900:Desoxycorticosterone / Q000009:adverse effects*; D004730:Endothelium, Vascular / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006973:Hypertension / Q000139:chemically induced / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D023421:Models, Animal; D009569:Nitric Oxide / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism*; D010100:Oxygen / Q000378:metabolism; D011622:Pterins / Q000494:pharmacology
chemical_list: D000098:Acetophenones; D004791:Enzyme Inhibitors; D011622:Pterins; D001708:Biopterins; D009569:Nitric Oxide; D003900:Desoxycorticosterone; C056165:acetovanillone; C016727:sepiapterin; D000429:Alcohol Oxidoreductases; C022630:sepiapterin reductase; D052250:Nitric Oxide Synthase Type III; C003402:sapropterin; D010100:Oxygen