ArticleJournal of molecular and cellular cardiology2011
Bi-modal dose-dependent cardiac response to tetrahydrobiopterin in pressure-overload induced hypertrophy and heart failure.
Article in Journal of molecular and cellular cardiology, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 22 papers.
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Who cites it
22 citing papers in PubMed, 44 citations in OpenAlex.
- Effects of Sapropterin on Portal and Systemic Hemodynamics in Patients With Cirrhosis and Portal Hypertension: A Bicentric Double-Blind Placebo-Controlled Study.The American journal of gastroenterology · 2015Trial
- Tetrahydrobiopterin paradoxically mediates cardiac oxidative stress and mitigates ethanol-evoked cardiac dysfunction in conscious female rats.European journal of pharmacology · 2021Article
- Combined l-citrulline and tetrahydrobiopterin therapy improves NO signaling and ameliorates chronic hypoxia-induced pulmonary hypertension in newborn pigs.American journal of physiology. Lung cellular and molecular physiology · 2020Article
- NADPH oxidases and oxidase crosstalk in cardiovascular diseases: novel therapeutic targets.Nature reviews. Cardiology · 2020Review
- Nitric oxide signalling in cardiovascular health and disease.Nature reviews. Cardiology · 2018Review
- Tetrahydrobiopterin oral therapy recouples eNOS and ameliorates chronic hypoxia-induced pulmonary hypertension in newborn pigs.American journal of physiology. Lung cellular and molecular physiology · 2016Article
- Increasing tetrahydrobiopterin in cardiomyocytes adversely affects cardiac redox state and mitochondrial function independently of changes in NO production.Free radical biology & medicine · 2016Article
- Tetrahydrobiopterin Protects Against Hypertrophic Heart Disease Independent of Myocardial Nitric Oxide Synthase Coupling.Journal of the American Heart Association · 2016Article
- Rescue of Heart Failure by Mitochondrial Recovery.International neurourology journal · 2016Review
- Celecoxib prevents pressure overload-induced cardiac hypertrophy and dysfunction by inhibiting inflammation, apoptosis and oxidative stress.Journal of cellular and molecular medicine · 2016Article
- Cardioprotective efficacy depends critically on pharmacological dose, duration of ischaemia, health status of animals and choice of anaesthetic regimen: a case study with folic acid.Journal of translational medicine · 2014Article
- Signaling by S-nitrosylation in the heart.Journal of molecular and cellular cardiology · 2014Review
- Tetrahydrobiopterin in cardiovascular health and disease.Antioxidants & redox signaling · 2014Review
- Cardiac oxidative stress in a mouse model of neutral lipid storage disease.Biochimica et biophysica acta · 2013Article
- Human endothelial dihydrofolate reductase low activity limits vascular tetrahydrobiopterin recycling.Free radical biology & medicine · 2013Article
- Heart failure with preserved ejection fraction: emerging drug strategies.Journal of cardiovascular pharmacology · 2013Review
- Nitric oxide synthases in heart failure.Antioxidants & redox signaling · 2013Review
- Rodent models of heart failure: an updated review.Heart failure reviews · 2013Review
- Tetrahydrobiopterin improves diastolic dysfunction by reversing changes in myofilament properties.Journal of molecular and cellular cardiology · 2013Article
- Mitochondria as a therapeutic target in heart failure.Journal of the American College of Cardiology · 2013Review
Corrections and comments
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Authors and funding
9 authors at 4 institutions in 2 countries.
Funding
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 0-400mg/kg/d BH4 by ingesting small pre-made pellets (consumed over 15-30 min). In a dose range of 36-200mg/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 400mg/kg/d, this lowered the BH4/BH2 ratio back toward 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. This article is part of a special issue entitled ''Key Signaling Molecules in Hypertrophy and Heart Failure.''
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