Tetrahydrobiopterin improves endothelial function in patients with cystic fibrosis

Jin Hee Jeong, Nichole Lee, Matthew A. Tucker, Paula Rodriguez-Miguelez, Jacob Looney, Jeffrey Thomas, Casandra C. Derella, Ahmed Abdelrazik Elmarakby, Jacqueline B. Musall, Jennifer C Sullivan, Kathleen T McKie, Caralee Johnson Forseen, Gareth W. Davison, Ryan A. Harris

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

Cystic fibrosis (CF) is a genetic disorder associated with vascular endothelial dysfunction. Nitric oxide (NO) plays a major role in maintaining vascular function, and tetrahydrobiopterin (BH4) is a critical determinant of NO bioavailability. Thus the purpose of this study was to investigate the effects of oral administration of BH4 on endothelial function in patients with CF. Twenty-nine patients with CF (18 8 yr old) and 29 healthy matched controls were recruited. Patients with CF participated in a randomized trial where they received a 5 mg/kg dose of oral BH4 (BH4-5; n 17) or a 20 mg/kg dose of oral BH4 (BH4-20; n 12). On a separate visit, a subset of patients from each group was retested following a placebo (PLC; n 9). Brachial artery flow-mediated dilation (FMD) was used to evaluate vascular endothelial function, and a plasma sample was obtained before and 3 h after treatment. Cultured endothelial cells were treated with plasma to assess NO bioavailability. Baseline FMD was lower in patients compared with controls (5.7 3.4 vs. 8.4 3.5%, respectively, P 0.005). No change in FMD was observed following PLC or BH 4 -5 (FMD: 0.8 1.9% and 0.5 2.5%; P 0.273 and 0.132, respectively). Treatment with BH4-20, however, resulted in significant improvements in FMD (FMD: 1.1 1.4%) compared with BH4-5 (P 0.023) and PLC (P 0.017). Moreover, BH4-20 significantly decreased endothelial cell superoxide production and increased NO production. These data suggest that a single oral dose of BH 4 at 20 mg/kg improves vascular endothelial function in patients with CF, likely via increased endothelial NO synthase coupling. These findings support the hypothesis that loss of BH4 bioactivity contributes, in part, to endothelial dysfunction in patients with CF.

Original languageEnglish (US)
Pages (from-to)60-66
Number of pages7
JournalJournal of Applied Physiology
Volume126
Issue number1
DOIs
StatePublished - Jan 1 2019

Fingerprint

Cystic Fibrosis
Dilatation
Blood Vessels
Nitric Oxide
Biological Availability
Endothelial Cells
Inborn Genetic Diseases
Brachial Artery
Nitric Oxide Synthase Type III
sapropterin
Superoxides
Oral Administration
Cultured Cells
Placebos
Therapeutics

Keywords

  • BH4
  • Cystic fibrosis
  • Dose-response
  • Flow-mediated dilation
  • Nitric oxide bioavailability

ASJC Scopus subject areas

  • Physiology
  • Physiology (medical)

Cite this

Tetrahydrobiopterin improves endothelial function in patients with cystic fibrosis. / Jeong, Jin Hee; Lee, Nichole; Tucker, Matthew A.; Rodriguez-Miguelez, Paula; Looney, Jacob; Thomas, Jeffrey; Derella, Casandra C.; Elmarakby, Ahmed Abdelrazik; Musall, Jacqueline B.; Sullivan, Jennifer C; McKie, Kathleen T; Forseen, Caralee Johnson; Davison, Gareth W.; Harris, Ryan A.

In: Journal of Applied Physiology, Vol. 126, No. 1, 01.01.2019, p. 60-66.

Research output: Contribution to journalArticle

Jeong, JH, Lee, N, Tucker, MA, Rodriguez-Miguelez, P, Looney, J, Thomas, J, Derella, CC, Elmarakby, AA, Musall, JB, Sullivan, JC, McKie, KT, Forseen, CJ, Davison, GW & Harris, RA 2019, 'Tetrahydrobiopterin improves endothelial function in patients with cystic fibrosis', Journal of Applied Physiology, vol. 126, no. 1, pp. 60-66. https://doi.org/10.1152/japplphysiol.00629.2018
Jeong, Jin Hee ; Lee, Nichole ; Tucker, Matthew A. ; Rodriguez-Miguelez, Paula ; Looney, Jacob ; Thomas, Jeffrey ; Derella, Casandra C. ; Elmarakby, Ahmed Abdelrazik ; Musall, Jacqueline B. ; Sullivan, Jennifer C ; McKie, Kathleen T ; Forseen, Caralee Johnson ; Davison, Gareth W. ; Harris, Ryan A. / Tetrahydrobiopterin improves endothelial function in patients with cystic fibrosis. In: Journal of Applied Physiology. 2019 ; Vol. 126, No. 1. pp. 60-66.
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abstract = "Cystic fibrosis (CF) is a genetic disorder associated with vascular endothelial dysfunction. Nitric oxide (NO) plays a major role in maintaining vascular function, and tetrahydrobiopterin (BH4) is a critical determinant of NO bioavailability. Thus the purpose of this study was to investigate the effects of oral administration of BH4 on endothelial function in patients with CF. Twenty-nine patients with CF (18 8 yr old) and 29 healthy matched controls were recruited. Patients with CF participated in a randomized trial where they received a 5 mg/kg dose of oral BH4 (BH4-5; n 17) or a 20 mg/kg dose of oral BH4 (BH4-20; n 12). On a separate visit, a subset of patients from each group was retested following a placebo (PLC; n 9). Brachial artery flow-mediated dilation (FMD) was used to evaluate vascular endothelial function, and a plasma sample was obtained before and 3 h after treatment. Cultured endothelial cells were treated with plasma to assess NO bioavailability. Baseline FMD was lower in patients compared with controls (5.7 3.4 vs. 8.4 3.5{\%}, respectively, P 0.005). No change in FMD was observed following PLC or BH 4 -5 (FMD: 0.8 1.9{\%} and 0.5 2.5{\%}; P 0.273 and 0.132, respectively). Treatment with BH4-20, however, resulted in significant improvements in FMD (FMD: 1.1 1.4{\%}) compared with BH4-5 (P 0.023) and PLC (P 0.017). Moreover, BH4-20 significantly decreased endothelial cell superoxide production and increased NO production. These data suggest that a single oral dose of BH 4 at 20 mg/kg improves vascular endothelial function in patients with CF, likely via increased endothelial NO synthase coupling. These findings support the hypothesis that loss of BH4 bioactivity contributes, in part, to endothelial dysfunction in patients with CF.",
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AU - Sullivan, Jennifer C

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