Stay in Shape With BH4
Loss of Endothelial Tetrahydrobiopterin Promotes Aortic Aneurysm Development in Mice
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See related article, pp 128–138
Tetrahydrobiopterin (BH4) is an interesting molecule. It has a complex redox chemistry, which involves auto-oxidation and antioxidant capacity of its degradation products1 and a clinical relevant function: deficiency in BH4, as present in the autosomal recessive inherited dihydropterindin reductase deficiency, results in hyperphenylalaninemia (phenylketonuria type 2) with mental retardation. BH4 is a redox-activated cofactor in 3 enzyme classes: for the hydroxylases of the 3 aromatic amino acids phenylalanine, tyrosine, and tryptophan; for either lipid oxidases; and for the 3 NOS (NO synthase) isoenzymes.1 In the cardiovascular system, the latter function in particular gained a lot of interest because deficiency or oxidation of BH4 results in NOS uncoupling, that is, the switching of NOS from an NO to a superoxide anion (O2−)-producing enzyme. The NOS of endothelial cells (eNOS) is of critical importance for normal vascular function, and loss of eNOS activity promotes hypertension and atherosclerosis.2 Lack of BH4, therefore, is a long-established mechanism of endothelial dysfunction.3 What on first sight appeared to be a simple story, however, gave rise to a long-lasting debate, which has only now been concluded.
Despite the fact that eNOS requires BH4, endothelial cells lack sufficient BH4 uptake mechanisms and are, therefore, critically dependent on BH4 de novo synthesis and recycling.4 …