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

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Oxidative Stress in Cancer Biology and Therapy

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Abstract

Radiation-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.

Financial Support:

National Institutes of Health/National Cancer Institute (grant CA83719 to MH-J) and Defense Threat Reduction Agency (grant HDTRA1-07-C-0028 to MH-J and H.10027-07-AR-R to KSK).

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Authors and Affiliations

  1. Department of Radiation Oncology (Maastro), Maastricht University Medical Center, 6229 ET, Maastricht, The Netherlands

    Maaike Berbée MD

  2. Division of Radiation Health, University of Arkansas for Medical Sciences, 4301 West Markham , Slot 522-10, Little Rock, AR, 72205, USA

    Qiang Fu MD, PhD & Martin Hauer-Jensen MD, PhD

  3. Armed Forces Radiobiology Research Institute, Uniformed Services University of the Health Sciences, Bethesda, MD, 20889, USA

    K. Sree Kumar PhD

Authors
  1. Maaike Berbée MD
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  2. Qiang Fu MD, PhD
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  3. K. Sree Kumar PhD
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  4. Martin Hauer-Jensen MD, PhD
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Corresponding author

Correspondence to Martin Hauer-Jensen MD, PhD .

Editor information

Editors and Affiliations

  1. Free Radical & Radiation Biology, Graduate Program, University of Iowa, Iowa City, 52242, Iowa, USA

    Douglas R. Spitz

  2. Duluth Clinic, Radiation Oncology, University of Minnesota, East 3rd Street 400, Duluth, 55805, Minnesota, USA

    Kenneth J. Dornfeld

  3. James H. Quillen College of Medicine, Internal Medicine, East Tennessee State University, Johnson City, 37614, Tennessee, USA

    Koyamangalath Krishnan

  4. Radiation Oncology, Cancer Biology and Pediatrics, Vanderbilt Medical School, 21st Ave. 1161, Nashville, 37232, Tennessee, USA

    David Gius

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Berbée, M., Fu, Q., Kumar, K.S., Hauer-Jensen, M. (2012). Tetrahydrobiopterin and Endothelial Nitric Oxide Synthase: Implications for Radiation-Induced Endothelial Dysfunction and Normal Tissue Radiation Injury. In: Spitz, D., Dornfeld, K., Krishnan, K., Gius, D. (eds) Oxidative Stress in Cancer Biology and Therapy. Oxidative Stress in Applied Basic Research and Clinical Practice. Humana Press, Totowa, NJ. https://doi.org/10.1007/978-1-61779-397-4_7

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