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(Hypertension. 2009;53:907.)
© 2009 American Heart Association, Inc.

Editorial Commentaries

Tetrahydrobiopterin, Endothelial Nitric Oxide Synthase, and Mitochondrial Function in the Heart

Johann Bauersachs; Julian D. Widder

From the Medizinische Klinik und Poliklinik I, Universitätsklinikum, Julius-Maximilians-Universität Würzburg, Germany.

Correspondence to Johann Bauersachs, Medizinische Klinik und Poliklinik I, Universitätsklinikum, Josef-Schneider-Str 2, D-97080 Würzburg, Germany. E-mail j.bauersachs@medizin.uni-wuerzburg.de

An extract of the first 250 words of the full text is provided, because this article has no abstract.

Tetrahydrobiopterin (BH₄) is an essential cofactor for the normal enzymatic function of endothelial NO synthase (eNOS) to produce NO, because it is involved in the catalytic process of L-arginine oxidation. Insufficient BH₄ availability impairs this process, and the free radical superoxide anion (O₂^·–) is released rather than NO, a condition termed "eNOS uncoupling."¹ BH₄, eNOS, and NO levels physiologically increase in parallel, as seen in response to shear stress, the most important physiological stimulus for endothelial NO production. Shear stress increases BH₄ through a casein kinase 2–dependent phosphorylation of GTP cyclohydrolase-1, the enzyme catalyzing the first step in BH₄ synthesis. Blockade of GTP cyclohydrolase-1 by the specific inhibitor 2,4-diamino-6-hydroxypyrimidine (DAHP) results in eNOS uncoupling in endothelial cells exposed to shear stress.² In transgenic mice overexpressing eNOS, a large portion of the enzyme is uncoupled because of BH₄ deficiency, leading to excessive endothelial formation of O₂^·–, which reacts rapidly to form peroxynitrite.³ Because BH₄ is highly sensitive to oxidation by the particular aggressive reactive oxygen species (ROS) peroxynitrite, in most cardiovascular disease states, BH₄ is depleted.⁴ Compelling evidence exists that eNOS uncoupling contributes to endothelial dysfunction in diabetes mellitus, atherosclerosis, and hypertension. NO is also an essential regulator of cardiac structure and function; however, only a few studies have investigated the role of BH₄ in this regard. Takimoto et al⁵ revealed the importance of BH₄ depletion for eNOS uncoupling and subsequent left ventricular hypertrophy in mice subjected to pressure overload. Exogenous BH₄ was able to recouple . . . [Full Text of this Article]

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