English Abstract, FWF Project 22289, Tetrahydrobiopterin and Ischemia-Reperfusion Injury,
Ernst R. Werner, Division of Biological Chemistry, Biocenter, Medical University of Innsbruck
Ischemia reperfusion injury remains a major quest despite several advances in organ preservation, in surgical techniques as well as in immunosuppressive therapy improving dramatically patient and graft survival. Especially in pancreas transplantation ischemia reperfusion injury associated graft pancreatitis is thought to be responsible for up to 10% of early graft losses.
In previous work we have observed that treatment of animals with tetrahydrobiopterin can dramatically reduce ischemia reperfusion injury in a murine model of pancreas ischemia reperfusion injury. Tetrahydrobiopterin is a compound structurally related to the vitamins folic acid and riboflavin, but endogenously synthesized in mammals. It acts as cofactor of aromatic amino acid hydroxylases, glyceryl ether monooxygenase and nitric oxide synthases. When tetrahydrobiopterin is partially oxidized in the body to dihydrobiopterin by oxidative stress, nitric oxide synthase is known to produce oxygen radicals rather than nitric oxide by uncoupling, a phenomenon that is thought to contribute not only to ischemia reperfusion injury, but also to vascular dysfunction in a variety of diseases such as diabetes.
In the present project we want to characterize the mechanisms leading to this beneficial effect of tetrahydrobiopterin. In a first approach, we want to compare the effect to other biological reducing agents and characterize which parts of the chemical structure of tetrahydrobiopterin are necessary for the observed effects. In a second approach, we want to test the influence of the three nitric oxide synthase isoforms on this effect with the help of mouse mutants lacking one of the three isoforms of nitric oxide synthase. In addition to standard clinical and biochemical parameters, we will use in vivo fluorescence microscopy to stain and quantify the microcirculation in the tissue and global protein and gene expression studies to get a comprehensive picture of the biochemical effects of treatment in dependence of the functional inactivation of a specific nitric oxide synthase isoform.
We expect that the results of this project will deepen our understanding of the biochemistry of ischemia reperfusion injury and its prevention, and provide the basis for pharmacological intervention to prevent ischemia reperfusion injury in clinical applications.
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