Bi-modal dose-dependent cardiac response to tetrahydrobiopterin in pressure-overload induced hypertrophy and heart failure

Abstract

The exogenous administration of tetrahydrobiopterin (BH4), an essential cofactor of nitric oxide synthase (NOS), has been shown to reduce left ventricular hypertrophy, fibrosis, and cardiac dysfunction in mice with pre-established heart disease induced by pressure-overload. In this setting, BH4 re-coupled endothelial NOS (eNOS), with subsequent reduction of NOS-dependent oxidative stress and reversal of maladaptive remodeling. However, recent studies suggest the effective BH4 dosing may be narrower than previously thought, potentially due to its oxidation upon oral consumption. Accordingly, we assessed the dose response of daily oral synthetic sapropterin dihydrochloride (6-R-L-erythro-5,6,7,8-tetrahydrobiopterin, 6R-BH4) on pre-established pressure-overload cardiac disease. Mice (n=64) were administered 0-400 mg/kg/d BH4 by ingesting small pre-made pellets (consumed over 15-30 min). In a dose range of 36-200 mg/kg/d, 6R-BH4 suppressed cardiac chamber remodeling, hypertrophy, fibrosis, and oxidative stress with pressure-overload. However, at both lower and higher doses, BH4 had less or no ameliorative effects. The effective doses correlated with a higher myocardial BH4/BH2 ratio. However, BH2 rose linearly with dose, and at the 400 mg/kg/d, this lowered the BH4/BH2 ratio back towards control. These results expose a potential limitation for the clinical use of BH4, as variability of cellular redox and perhaps heart disease could produce a variable therapeutic window among individuals.

Nitric Oxide Synthases in Heart Failure

“…Pharmacological supplementation of BH4 improves endothelium-dependent relaxation and NOS coupling (155,157). BH4 aids electron transfer from the NOS reductase to the oxidase domains, assisting in the production of NO and L-citrulline from L-arginine.…”

“…Another factor is that orally consumed BH4 is rapidly oxidized, and should be reconverted by DHFR to be effective. Even in mice, where exogenous BH4 is effective for treating heart disease, increasing the dose led to a paradox reversal of benefit, re-appearance of ROS, and this was coupled with a decline in the BH4/BH2 ratio toward baseline (155). Variability in both uptake and redox modification of exogenous BH4 depending on the patient and disease would greatly complicate its clinical pharmacology.…”

Rodent models of heart failure: an updated review

“…Additionally, the exogenous administration of the NOS cofactor BH4 has been shown to reduce LV hypertrophy, fibrosis and cardiac dysfunction in mice with pre-established pressure overload. In this setting, BH4 recoupled endothelial NOS, with subsequent reduction of NOS-dependent oxidative stress and reversal of maladaptive remodeling [195,196].…”

Decreased cardiac mitochondrial tetrahydrobiopterin in a rat model of pressure overload

“…Malo et al (11) reported that treatment with BH4 prevented endothelial dysfunction in epicardial coronary arteries associated with left ventricular hypertrophy in a porcine model. Moreover, administration of BH4 has been shown to protect the myocardium against pressure overload, resulting in the improvement of fibrosis, cardiac dysfunction and hypertrophy (12)(13)(14). Takimoto et al (15) showed that pressure overload triggers NOS3 uncoupling as a prominent source of myocardial ROS contributing to dilatory remodeling and cardiac dysfunction using NOS3-deficient mice.…”