Author + information
- Received August 8, 2017
- Revision received October 27, 2017
- Accepted January 24, 2018
- Published online June 25, 2018.
- Lamia Heikal, PhDa,
- Anna Starr, PhDa,
- Dania Hussein, PhDa,
- Jesus Prieto-Lloret, PhDb,
- Phil Aaronson, PhDb,
- Lea Ann Dailey, PhDa and
- Manasi Nandi, PhDa,c,∗ ()
- aInstitute of Pharmaceutical Sciences, Faculty of Life Sciences and Medicine, King’s College London, London, United Kingdom
- bDivision of Asthma, Faculty of Life Sciences and Medicine, King’s College London, London, United Kingdom
- cCardiovascular Division, Faculty of Life Sciences and Medicine, King’s College London, London, United Kingdom
- ↵∗Address for correspondence:
Dr. Manasi Nandi, Pharmacology and Therapeutics, Faculty of Life Sciences and Medicine, King’s College London, 150 Stamford Street, London SE1 9NH, United Kingdom.
• Tetrahydrobiopterin is an essential cofactor for NO production.
• Limitation of endogenous tetrahydrobiopterin reduces NO bioavailability, enhances oxidative stress, and impairs vascular function.
• Orally supplemented tetrahydrobiopterin has therapeutic challenges because it is rapidly oxidized in vivo.
• Here, the authors demonstrate that l-phenylalanine, when administered orally, raises vascular tetrahydrobiopterin, restores NO, reduces superoxide, and enhances vascular function in spontaneously hypertensive rats.
• This effect is achieved by activation of a protein complex (GCH1-GFRP) involved in the biosynthesis of tetrahydrobiopterin.
• Activation of this protein complex by l-phenylalanine or its analogues represents a novel therapeutic target for vascular disorders underpinned by reduced NO bioavailability.
Reduced nitric oxide (NO) bioavailability correlates with impaired cardiovascular function. NO is extremely labile and has been challenging to develop as a therapeutic agent. However, NO bioavailability could be enhanced by pharmacologically targeting endogenous NO regulatory pathways. Tetrahydrobiopterin, an essential cofactor for NO production, is synthesized by GTP cyclohydrolase-1 (GCH1), which complexes with GCH1 feedback regulatory protein (GFRP). The dietary amino acid l-phenylalanine activates this complex, elevating vascular BH4. Here, the authors demonstrate that l-phenylalanine administration restores vascular function in a rodent model of hypertension, suggesting the GCH1-GFRP complex represents a rational therapeutic target for diseases underpinned by endothelial dysfunction.
The work was funded by The Maplethorpe Trust Fellowship and British Heart Foundation PG/09/073. The authors have reported that they have no relationships relevant to the contents of this paper to disclose.
All authors attest they are in compliance with human studies committees and animal welfare regulations of the authors’ institutions and Food and Drug Administration guidelines, including patient consent where appropriate. For more information, visit the JACC: Basic to Translational Science author instructions page.
- Received August 8, 2017.
- Revision received October 27, 2017.
- Accepted January 24, 2018.
- 2018 The Authors