Acute Tetrahydrobiopterin Improves Endothelial Function in Patients With COPD

Paula Rodriguez-Miguelez, Justin Gregg, Nichole Seigler, Leon Bass, Jeffrey Thomas, Jennifer S. Pollock, Jennifer C Sullivan, Thomas A Dillard, Ryan A. Harris

Research output: Contribution to journalArticle

Abstract

Background: Cardiovascular diseases represent a hallmark characteristic in COPD, and endothelial dysfunction has been observed in these patients. Tetrahydrobiopterin (BH4) is an essential cofactor for nitric oxide (NO) synthesis and a regulator of endothelial function. The goal of this study was to test the hypothesis that a single dose of BH4 would improve endothelial function in patients with COPD via an increase in NO bioavailability. Methods: Seventeen patients with COPD completed a randomized, double-blind, placebo (PLC)-controlled, crossover trial with an acute dose of either BH4 (Kuvan; BioMarin Pharmaceutical Inc) or PLC. Flow-mediated dilation (FMD), a bioassay of endothelial function, was completed prior to and 3 h following each treatment. Phospho- and total endothelial NO synthase (NOS3) protein was evaluated after incubating endothelial cells with plasma from the patients prior to and following treatment. Fifteen demographically matched control subjects were tested at baseline for case control comparisons. Results: Treatment with BH4 significantly (P ≤.004) increased FMD, improving endothelial function in patients compared to control values (P ≥.327). BH4 increased (P =.013) the ratio of phospho-NOS3 to total NOS3 protein. No changes in FMD (P ≥.776) or the protein ratio (P =.536) were observed following PLC. Conclusions: An acute dose of BH4 was able to improve endothelial function in patients with COPD to values similar to control subjects. The improvement in endothelial function was accompanied by an increase in NOS3 phosphorylation. BH4 may represent a potential novel therapy to improve endothelial function and reduce cardiovascular disease risk in patients with COPD. Trial Registry: ClinicalTrials.gov; No.: NCT01398943; URL: www.clinicaltrials.gov.

LanguageEnglish (US)
Pages597-606
Number of pages10
JournalCHEST
Volume154
Issue number3
DOIs
StatePublished - Sep 1 2018

Fingerprint

Chronic Obstructive Pulmonary Disease
Dilatation
Placebos
Nitric Oxide
Cardiovascular Diseases
Proteins
Nitric Oxide Synthase Type III
Therapeutics
sapropterin
Biological Assay
Cross-Over Studies
Biological Availability
Registries
Endothelial Cells
Phosphorylation
Pharmaceutical Preparations

Keywords

  • BH
  • COPD
  • endothelial function
  • FMD
  • NOS3

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine
  • Critical Care and Intensive Care Medicine
  • Cardiology and Cardiovascular Medicine

Cite this

Rodriguez-Miguelez, P., Gregg, J., Seigler, N., Bass, L., Thomas, J., Pollock, J. S., ... Harris, R. A. (2018). Acute Tetrahydrobiopterin Improves Endothelial Function in Patients With COPD. CHEST, 154(3), 597-606. https://doi.org/10.1016/j.chest.2018.04.028

Acute Tetrahydrobiopterin Improves Endothelial Function in Patients With COPD. / Rodriguez-Miguelez, Paula; Gregg, Justin; Seigler, Nichole; Bass, Leon; Thomas, Jeffrey; Pollock, Jennifer S.; Sullivan, Jennifer C; Dillard, Thomas A; Harris, Ryan A.

In: CHEST, Vol. 154, No. 3, 01.09.2018, p. 597-606.

Research output: Contribution to journalArticle

Rodriguez-Miguelez, P, Gregg, J, Seigler, N, Bass, L, Thomas, J, Pollock, JS, Sullivan, JC, Dillard, TA & Harris, RA 2018, 'Acute Tetrahydrobiopterin Improves Endothelial Function in Patients With COPD' CHEST, vol. 154, no. 3, pp. 597-606. https://doi.org/10.1016/j.chest.2018.04.028
Rodriguez-Miguelez P, Gregg J, Seigler N, Bass L, Thomas J, Pollock JS et al. Acute Tetrahydrobiopterin Improves Endothelial Function in Patients With COPD. CHEST. 2018 Sep 1;154(3):597-606. https://doi.org/10.1016/j.chest.2018.04.028
Rodriguez-Miguelez, Paula ; Gregg, Justin ; Seigler, Nichole ; Bass, Leon ; Thomas, Jeffrey ; Pollock, Jennifer S. ; Sullivan, Jennifer C ; Dillard, Thomas A ; Harris, Ryan A. / Acute Tetrahydrobiopterin Improves Endothelial Function in Patients With COPD. In: CHEST. 2018 ; Vol. 154, No. 3. pp. 597-606.
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abstract = "Background: Cardiovascular diseases represent a hallmark characteristic in COPD, and endothelial dysfunction has been observed in these patients. Tetrahydrobiopterin (BH4) is an essential cofactor for nitric oxide (NO) synthesis and a regulator of endothelial function. The goal of this study was to test the hypothesis that a single dose of BH4 would improve endothelial function in patients with COPD via an increase in NO bioavailability. Methods: Seventeen patients with COPD completed a randomized, double-blind, placebo (PLC)-controlled, crossover trial with an acute dose of either BH4 (Kuvan; BioMarin Pharmaceutical Inc) or PLC. Flow-mediated dilation (FMD), a bioassay of endothelial function, was completed prior to and 3 h following each treatment. Phospho- and total endothelial NO synthase (NOS3) protein was evaluated after incubating endothelial cells with plasma from the patients prior to and following treatment. Fifteen demographically matched control subjects were tested at baseline for case control comparisons. Results: Treatment with BH4 significantly (P ≤.004) increased FMD, improving endothelial function in patients compared to control values (P ≥.327). BH4 increased (P =.013) the ratio of phospho-NOS3 to total NOS3 protein. No changes in FMD (P ≥.776) or the protein ratio (P =.536) were observed following PLC. Conclusions: An acute dose of BH4 was able to improve endothelial function in patients with COPD to values similar to control subjects. The improvement in endothelial function was accompanied by an increase in NOS3 phosphorylation. BH4 may represent a potential novel therapy to improve endothelial function and reduce cardiovascular disease risk in patients with COPD. Trial Registry: ClinicalTrials.gov; No.: NCT01398943; URL: www.clinicaltrials.gov.",
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AB - Background: Cardiovascular diseases represent a hallmark characteristic in COPD, and endothelial dysfunction has been observed in these patients. Tetrahydrobiopterin (BH4) is an essential cofactor for nitric oxide (NO) synthesis and a regulator of endothelial function. The goal of this study was to test the hypothesis that a single dose of BH4 would improve endothelial function in patients with COPD via an increase in NO bioavailability. Methods: Seventeen patients with COPD completed a randomized, double-blind, placebo (PLC)-controlled, crossover trial with an acute dose of either BH4 (Kuvan; BioMarin Pharmaceutical Inc) or PLC. Flow-mediated dilation (FMD), a bioassay of endothelial function, was completed prior to and 3 h following each treatment. Phospho- and total endothelial NO synthase (NOS3) protein was evaluated after incubating endothelial cells with plasma from the patients prior to and following treatment. Fifteen demographically matched control subjects were tested at baseline for case control comparisons. Results: Treatment with BH4 significantly (P ≤.004) increased FMD, improving endothelial function in patients compared to control values (P ≥.327). BH4 increased (P =.013) the ratio of phospho-NOS3 to total NOS3 protein. No changes in FMD (P ≥.776) or the protein ratio (P =.536) were observed following PLC. Conclusions: An acute dose of BH4 was able to improve endothelial function in patients with COPD to values similar to control subjects. The improvement in endothelial function was accompanied by an increase in NOS3 phosphorylation. BH4 may represent a potential novel therapy to improve endothelial function and reduce cardiovascular disease risk in patients with COPD. Trial Registry: ClinicalTrials.gov; No.: NCT01398943; URL: www.clinicaltrials.gov.

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