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

An L. Moens, Elizabeth A. Ketner, Eiki Takimoto, Tim S. Schmidt, Charles A. O'Neill, Michael S. Wolin, Nicholas J. Alp, Keith M. Channon, David A Kass

Research output: Contribution to journalArticle

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 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".

Original languageEnglish (US)
Pages (from-to)564-569
Number of pages6
JournalJournal of Molecular and Cellular Cardiology
Volume51
Issue number4
DOIs
StatePublished - Oct 2011

Fingerprint

Hypertrophy
Heart Failure
Pressure
Heart Diseases
Nitric Oxide Synthase
Oxidative Stress
Fibrosis
Nitric Oxide Synthase Type III
Left Ventricular Hypertrophy
Oxidation-Reduction
sapropterin
Therapeutics

Keywords

  • Mouse models
  • Nitric oxide synthase
  • NOS-uncoupling
  • Oxidative stress
  • Pressure-overload
  • Tetrahydrobiopterin

ASJC Scopus subject areas

  • Molecular Biology
  • Cardiology and Cardiovascular Medicine

Cite this

Bi-modal dose-dependent cardiac response to tetrahydrobiopterin in pressure-overload induced hypertrophy and heart failure. / Moens, An L.; Ketner, Elizabeth A.; Takimoto, Eiki; Schmidt, Tim S.; O'Neill, Charles A.; Wolin, Michael S.; Alp, Nicholas J.; Channon, Keith M.; Kass, David A.

In: Journal of Molecular and Cellular Cardiology, Vol. 51, No. 4, 10.2011, p. 564-569.

Research output: Contribution to journalArticle

Moens, An L. ; Ketner, Elizabeth A. ; Takimoto, Eiki ; Schmidt, Tim S. ; O'Neill, Charles A. ; Wolin, Michael S. ; Alp, Nicholas J. ; Channon, Keith M. ; Kass, David A. / Bi-modal dose-dependent cardiac response to tetrahydrobiopterin in pressure-overload induced hypertrophy and heart failure. In: Journal of Molecular and Cellular Cardiology. 2011 ; Vol. 51, No. 4. pp. 564-569.
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AU - Moens, An L.

AU - Ketner, Elizabeth A.

AU - Takimoto, Eiki

AU - Schmidt, Tim S.

AU - O'Neill, Charles A.

AU - Wolin, Michael S.

AU - Alp, Nicholas J.

AU - Channon, Keith M.

AU - Kass, David A

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AB - 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 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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