title: Tetrahydrobiopterin deficiency exaggerates intimal hyperplasia after vascular injury.
abstract: Decreased levels of tetrahydrobiopterin (BH4), an absolute cofactor for nitric oxide synthase (NOS), lead to uncoupling of NOS into a superoxide v. nitric oxide producing enzyme, and it is this uncoupling that links it to the development of vascular disease. However, the effects of in vivo deficiency of BH4 on neointimal formation after vascular injury have not been previously investigated. Hph-1 mice, which display 90% deficiency in guanine triphosphate cyclohydrolase I, the rate limiting enzyme in BH4 synthesis, were used. Hph-1 and wild-type mice, treated with either vehicle or BH4 (n = 15 per group), were subjected to wire-induced femoral artery injury, and NOS expression and activity, inflammation, cell proliferation, superoxide production, and neointimal formation were assessed. The major form of NOS expressed over vessel wall after vascular injury was endothelial NOS. Hph-1 mice exhibited lower NOS activity (2.8 +/- 0.3 vs. 4.5 +/- 0.4 pmol/min/mg protein, P < 0.01), and higher aortic superoxide content (5.2 +/- 2.0 x 10(5) cpm vs. 1.6 +/- 0.7 x 10(5) cpm, P < 0.01) compared with wild-type controls, indicating uncoupling of NOS. Treatment of hph-1 mice with BH4 significantly increased NOS activity (from 2.8 +/- 0.3 to 4.1 +/- 0.4 pmol.min(-1).mg protein(-1), P < 0.05), and attenuated superoxide production (from 5.2 +/- 2.0 x 10(5) cpm to 0.8 +/- 0.7 x 10(5) cpm, P < 0.05). Hph-1 mice also had higher inflammatory reactions and more cell proliferation after vascular injury. Furthermore, hph-1 mice responded by a marked increase in neointimal formation at 4 wk after vascular injury, compared with wild-type controls (intima:media ratio: 4.5 +/- 0.5 vs. wild-type 0.7 +/- 0.1, P < 0.001). Treatment of hph-1 mice with BH4 prevented vascular injury-induced increase in neointimal formation (intima:media ratio: 1.4 +/- 0.1 vs. hph-1, P < 0.001). Treatment had no effect on wild-type controls. In summary, we describe, for the first time, that in vivo BH4 deficiency facilitates neointimal formation after vascular injury. Modulation of BH4 bioavailability is an important therapeutic target for restenosis.
authors.affiliation: Division of Cardiac Surgery, St. Michael's Hospital, 30 Bond St., Queen Wing, Suite 8-003H, Toronto, Ontario, Canada M5B 1W8.
authors.forename: Chao-Hung
authors.initials: CH
authors.lastname: Wang
authors.forename: Shu-Hong
authors.initials: SH
authors.lastname: Li
authors.forename: Richard D
authors.initials: RD
authors.lastname: Weisel
authors.forename: Paul W M
authors.initials: PW
authors.lastname: Fedak
authors.forename: Agnes
authors.initials: A
authors.lastname: Hung
authors.forename: Ren-Ke
authors.initials: RK
authors.lastname: Li
authors.forename: Vivek
authors.initials: V
authors.lastname: Rao
authors.forename: Keith
authors.initials: K
authors.lastname: Hyland
authors.forename: Wen-Jin
authors.initials: WJ
authors.lastname: Cherng
authors.forename: Lee
authors.initials: L
authors.lastname: Errett
authors.forename: Yves
authors.initials: Y
authors.lastname: Leclerc
authors.forename: Daniel
authors.initials: D
authors.lastname: Bonneau
authors.forename: David A
authors.initials: DA
authors.lastname: Latter
authors.forename: Subodh
authors.initials: S
authors.lastname: Verma
mesh_terms: D000818:Animals; D001011:Aorta / Q000201:enzymology / Q000378:metabolism; D001708:Biopterins / Q000031:analogs & derivatives* / Q000172:deficiency / Q000494:pharmacology; D049109:Cell Proliferation / Q000187:drug effects; D005263:Femoral Artery / Q000293:injuries* / Q000378:metabolism / Q000473:pathology*; D006965:Hyperplasia; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D008817:Mice, Mutant Strains; D019001:Nitric Oxide Synthase / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; D013481:Superoxides / Q000378:metabolism; D017539:Tunica Intima / Q000187:drug effects / Q000473:pathology*; D014657:Vasculitis / Q000209:etiology / Q000473:pathology; D014947:Wounds and Injuries / Q000150:complications / Q000378:metabolism / Q000473:pathology
chemical_list: D013481:Superoxides; D001708:Biopterins; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; C496317:Nos2 protein, mouse; C496315:Nos3 protein, mouse; C003402:sapropterin