Summary Report, FWF Project P22289, Tetrahydrobiopterin and Ischemia-reperfusion injury,
Ernst R. Werner, Divison of Biological Chemistry, Biocenter, Medical University of Innsbruck
Aim of this project was to describe the mode of action of tetrahydrobiopterin in preventing ischemia-reperfusion injury. We found that the neuronal isoform of nitric oxide synthase is a main inducer of ischemia reperfusion injury in the pancreas.
Ischemia-reperfusion injury occurs when an organ is disconnected from the blood flow, e.g. to be transplanted to another individual. As the designation already suggests, much of the damage occurs when the organ is reconnected to the blood flow (reperfusion), e.g. after implantation of the organ. The ischemia-reperfusion injury is one of the major issues limiting the quality and the life span of transplantation organs. Therefore, the way how this damage occurs is intensively studied, and means to avoid this damage are searched for.
Tetrahydrobiopterin is a compound with structural similarity to the vitamins folic acid and riboflavin. In contrast to these, however, it can be formed in our bodies. It is required to degrade the essential amino acid phenylalanine, to form the neurotransmitters dopamine and serotonin, and to make the signal molecule nitric oxide. Nitric oxide is formed by the enzyme nitric oxide synthase which occurs in three isoforms. The neuronal isoform is important for neurons and the brain. The endothelial isoform is located in the vessel wall and regulates the blood pressure. A third form plays an important role in the immune system’s defense against pathogens.
As a main result of our work we found that the neuronal isoform of nitric oxide synthase, not the endothelial isoform as expected, is a major player in ischemia-reperfusion injury. If this enzyme is absent, the mesh of blood capillaries in the pancreas shows almost no damage after taking out the organ, storing it, and implanting it again. The transplanted organs worked fine throughout the observation period. Nitric oxide synthase needs the vitamin-like compound tetrahydrobiopterin to function properly. If this compound is missing, the enzyme will produce highly toxic compounds derived from oxygen which damage the organ. Tetrahydrobiopterin is a labile compound which is destroyed by disconnection of the organ from the blood flow, causing the neuronal isoform of nitric oxide in the pancreas to form the toxic compounds derived from oxygen. If a single dose of tetrahydrobiopterin is applied before taking out the organ, this does not happen and the organ is not damaged. Likewise, if the enzyme is missing, this damage also does not occur.
Our findings describe novel processes leading to damages in transplanted organs. We have identified a new, major metabolic player resulting in damaged organs. We hope therefore, that our research will help in the development of drugs to improve the quality and lifespan of transplanted organs in the future.
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