Desferal Administration to Improve the Impaired Reaction to Hypoxia in Diabetes

Background Complications of diabetes represent the main concern for modern diabetes therapy, and it has become a priority to further characterize the pathophysiological mechanisms of these complications to ensure the development of novel rational therapeutic strategies.

Although the prolonged exposure of tissues to hyperglycemia is the primary causative factor for chronic diabetes complications, it has recently become increasingly evident that hypoxia also plays an important role in all diabetes complication. A low tissue concentration of oxygen in diabetes is the consequence of several mechanisms (e.g., deficient blood supply secondarily to micro- and macro-vascular disease, poor local oxygen diffusion secondarily to local edema or as a result of increased oxygen consumption).

Adaptive responses of the cells to hypoxia are mediated by Hypoxia-Inducible Factor 1 (HIF), which is a heterodimeric transcription factor, composed of two subunits (alfa and beta subunit) both constitutively expressed in mammalian cells. In normoxia, HIF-1α is continually degraded by the ubiquitin-proteasome system as a consequence of the oxygen-dependent hydroxylation of two key proline residues catalyzed by a group of enzymes called prolyl-hydroxylases (PHDs). Under hypoxia when the degradation pathway is suppressed and HIF-1α is stabilized, it translocates in the nucleus where it induces more than 800 genes that are

involved in angiogenesis, glycolytic energy metabolism, cell proliferation and survival that enable the cells to adapt to reduced oxygen availability. HIF-1 is central for expression of several angiogenic growth factors (ex. as Vascular Endothelial Growth Factor (VEGF), erythropoietin (EPO), and stromal cell-derived factor-1α (SDF-1α) and for endothelial progenitor cells (EPC) recruitment. Recently, it has been proposed that microRNAs (ex. mir210) also mediate a part of the HIF-1 functions.

PHDs that control the HIF 1 α stability and function are Fe 2+ and/or O2 -dependent enzymes and their activity could be inhibited by depleting the iron. Deferoxamine (DFO), which is an iron chelator induces therefore HIF-1α accumulation and hypoxia-response genes in normoxia both in vitro and in vivo being able to restore the repressed adaptative reaction to hypoxia different animal models of diabetes. DFO has been in clinical use for decades for treating excessive iron deposition secondary to different pathologies (thalassemia, myelosclerosis etc) and was used as pharmacological tool to induce HIF dependent responses.