Tetrahydrobiopterin and Endothelial Nitric Oxide Synthase: Implications for Radiation-Induced Endothelial Dysfunction and Normal Tissue Radiation Injury

Abstract

AbstractRadiation-induced microvascular injury plays an important role in the mechanisms of acute, as well as chronic normal tissue radiation toxicities. There is currently a growing body of evidence suggesting that depletion of the nitric oxide synthase (NOS) cofactor, 5,6,7,8-tetrahydrobiopterin (BH4) is involved in the pathogenesis of endothelial dysfunction in many disorders. BH4 is an essential cofactor for all NOS enzymes, which, in the presence of adequate amounts of BH4, produce mainly nitric oxide (NO). Under conditions of BH4 deficiency, however, NOS is in the “uncoupled” state and production shifts to highly reactive oxygen radicals, superoxide, and peroxynitrite, at the expense of NO. Excessive oxidative stress, which occurs after exposure to ionizing radiation, reduces the bioavailability of BH4 because of rapid oxidation to 7,8-dihydrobiopterin (7,8-BH2). Free radical-induced BH4 insufficiency may thus further increase oxidative stress locally, inhibit beneficial NO-dependent endothelial processes, and contribute to the development of endothelial dysfunction. Given that BH4 depletion and subsequent endothelial NOS uncoupling appear to play a major role in the pathogenesis of endothelial dysfunction in a number of disease processes, there is substantial reason to believe that improving postirradiation BH4 bioavailability, either by exogenous supplementation of BH4 or by modulating BH4 metabolism, might be a novel strategy by which radiation-induced endothelial dysfunction and subsequent tissue injury could be reduced. This chapter presents evidence to support the therapeutic potential of BH4 as a biological modulator of radiation toxicity.KeywordsNitric OxideEndothelial DysfunctionRadiation InjuryVascular RelaxationeNOS UncoupleThese keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.