Mechanisms and meaning of activation of Hypoxia-Inducible-Factor-1 (HIF-1) in muscle after mechanical trauma

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Hypoxia inducible factor 1 (HIF-1) is the key regulatory transcription factor that ensures adequate adaptation of hypoxic tissue to the shortage of oxygen. HIF-1 regulated genes cover iron and energy metabolism, vasomotor tone, vascular development and remodeling and oxygen capacity of the blood. In addition to hypoxia, mediators released from damaged tissue, i.e. reactive O2- and N2-species and cytokines, can activate HIF-1. In an animal model as well as cell culture studies the extent and the mechanisms of HIF-1 activation by hypoxia/reoxygenation as well as the above mentioned non-hypoxic stimuli will be investigated. By in vivo 2-photon and 1-photon multifocal laser microscopy the tissue response after trauma with respect to HIF-1 target genes will be monitored and modified by local constitutively active HIF-1 overexpression. In mice with a tissue specific HIF-1 knock-out consequences of the lack of HIF-1 will be studied. In close cooperation with other partners of the SPP 1151 specifically potential mediators of trauma as well as tissue specimen from patients will be included in our study. Our findings on the role of HIF-1 in mechanical muscle trauma could provide the basis for new therapeutic concepts of tissue repair after severe trauma.