Tetrahydrobiopterin improves endothelial function in patients with cystic fibrosis

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 BH4-5 (∆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 BH4 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. NEW & NOTEWORTHY For the first time, the present study documents that a single dose of oral BH4 can improve vascular endothelial function in patients with cystic fibrosis (CF), and our in vitro data suggest this is via decreasing uncoupled nitric oxide. These data provide insight into the important role of BH4 bioactivity in vascular dysfunction and provide the foundation for further investigation into the chronic effects of BH4 treatment in patients with CF.

New Therapeutic Implications of Endothelial Nitric Oxide Synthase (eNOS) Function/Dysfunction in Cardiovascular Disease

“…In a double-blind multicenter clinical trial 40 patients with cirrhosis and portal hypertension either received sapropterin (5 mg/kg/d for two weeks) or placebo, but hepatic blood flow, systemic hemodynamics, endothelial dysfunction markers, and liver function tests remained unchanged [238]. Other small cohort trials reported that a single oral dose of 10–20 mg/kg/d BH 4 improves endothelial function in patients with cystic fibrosis or healthy subjects (58 subjects) [239], 12 patients with systemic sclerosis [240] and 33 patients with rheumatoid arthritis [241], just to mention some of them. Supra-nutritional doses of folate seem to prevent and help to control diabetic complications [242].…”

The role of endothelial cells in cystic fibrosis

“…In the same study, a positive relationship between microvascular function and lung function was found suggesting that disease severity may contribute, at least in part, to microvascular dysfunction [ 34 ]. In follow-up studies, the same group demonstrated that four weeks treatment with sildenafil (an inhibitor of phosphodiesterase 5 that enhances NO metabolism) [ 35 ] and tetrahydrobiopterin (BH 4 , a determinant of NO bioavailability) [ 36 ] increased FMD in patients with CF. In vitro treatment of human umbilical vein endothelial cells (HUVEC) with CFTR inhibitor suppressed insulin-induced NO generation, by inhibiting eNOS and AKT activation/phosphorylation [ 37 ].…”

“…Stimulated superoxide production was significantly lower in ECs pre-incubated with plasma from patients with CF treated with BH 4 compared to ECs treated with pre-treatment plasma [ 36 ]. In an in vitro system using HUVEC, decreased CFTR expression led to increased oxidative stress ( Fig.…”

CFTR limits F‐actin formation and promotes morphological alignment with flow in human lung microvascular endothelial cells

“…In CF, defective flowmediated dilation (FMD) of the brachial artery suggests NO bioavailability is reduced in response to shear stress (Poore et al, 2013), and improved by agents that increase NO availability (Rodriguez-Miguelez et al, 2018). This notion is further supported by the observation that acute supplementation with 20 mg/kg of oral tetrahydrobiopterin (an essential cofactor for eNOS activity) significantly improved FMD, through reduced superoxide production and increased NO, which is indicative of improved eNOS coupling in people with CF (Jeong et al, 2018).…”