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• W14568424 abstract "Diabetic foot ulcers (DFU) represent one of the most feared and invalidating complication of diabetes with high financial pressure for the healthcare system. For the moment there is no specific therapy available and it has become a priority to develop novel rational therapeutic strategies based on new pathophysiological mechanisms. Our focus was therefore to delineate relevant pathogenic pathways specifically deregulated in diabetes that could contribute to the defective wound healing in diabetes. Cellular proliferation, migration and differentiation, angiogenesis, extracellular matrix deposition, local recruitment of endothelial precursors cells are some of the essential processes activated during wound healing. We decided to focus our investigation on two central signaling pathways (HIF-1 pathway and Notch signaling) that modulates most of the above cellular events. Hypoxia plays an important role in the development of DFU. We showed that hyperglycemia complexly repressed the function of Hypoxia inducible Factor (HIF) which is the main cellular adaptor to low oxygen tension. The repressive effect of hyperglycemia on HIF-1 alpha was pVHL dependent and affected complexly its transactivation. This was mirrored by suppression of several HIF-1 target genes essential for wound healing. However, by blocking HIFchemical interference with HIF hydroxylases (DMOG or DFX), it was possible to reverse the repressive effect of hyperglycemia on HIF and to improve the wound healing process in a diabetic mouse model (the db/db mouse). Moreover, local adenovirus-mediated transfer of two stable HIF constructs demonstrated that stabilization of HIF-1alpha is necessary and sufficient for promoting wound healing in a diabetic environment. Hyperbaric oxygen therapy (HBOT) has been used as therapeutical option for severe foot ulcers, resistant to standard therapy. The detailed mechanisms activated by HBOT are however still unraveled. We showed that HBOT activated HIF-1alpha at several levels with functional consequence on cellular proliferation. Moreover, we could show that local transfer of a stable form of HIF has additive effect to HBOT improving wound healing in the db/db mice. Notch signaling is a cell-to-cell contact system that consists of several receptors (Notch 1-4) and ligands with a high specific cell-dependent effect. Binding of the ligands to the receptors is followed by proteolytic cleavage of the receptor by a -secretase complex which is followed by activation of the intracellular signaling. Here we show that hyperglycemia activated Notch signaling at several levels both in vitro and in vivo. The effect of hyperglycemia on Notch signaling is canceled in the presence of -secretase inhibitors with positive functional effect both on in vitro migration and on in vitro angiogenesis assays. Moreover local treatment with -secretase inhibitors improved wound healing of db/db mice despite chronic hyperglycemia. The effect is specific -secretase inhibitors nor immunization with a DNA vaccine against Dll4 influenced the wound healing in non-diabetic animals. Using a loss of function genetic approach (specific siRNA and cre/lox system) we showed that Notch 1 has a central pathogenic role in Notch dependent repression of wound healing in diabetes. In conclusion, we identified two new pathogenic mechanisms important for impaired wound healing in diabetes. Our findings warrant development of specific therapeutics that address HIF and Notch signaling for normal healing of diabetic wounds. LIST OF PUBLICATIONS I. Botusan IR*, Sunkari VG*, Savu O, Catrina AI, Grunler J, Lindberg S, Pereira T, Yla-Herttuala S, Poellinger L, Brismar K, Catrina SB. Stabilization of HIF-1alpha is critical to improve wound healing in" @default.
• W14568424 created "2016-06-24" @default.
• W14568424 creator A5070282892 @default.
• W14568424 date "2012-11-01" @default.
• W14568424 modified "2023-09-27" @default.
• W14568424 title "New pathogenic mechanisms in diabetic wound healing" @default.
• W14568424 cites W124140706 @default.
• W14568424 cites W130424401 @default.
• W14568424 cites W1483725891 @default.
• W14568424 cites W1483762900 @default.
• W14568424 cites W1490068297 @default.
• W14568424 cites W1495287184 @default.
• W14568424 cites W1497205269 @default.
• W14568424 cites W1508234976 @default.
• W14568424 cites W1554209941 @default.
• W14568424 cites W1577847062 @default.
• W14568424 cites W1578283200 @default.
• W14568424 cites W1578887386 @default.
• W14568424 cites W1579881301 @default.
• W14568424 cites W1582872317 @default.
• W14568424 cites W1602050522 @default.
• W14568424 cites W1660631781 @default.
• W14568424 cites W1740257755 @default.
• W14568424 cites W1749022239 @default.
• W14568424 cites W1793808483 @default.
• W14568424 cites W1858509526 @default.
• W14568424 cites W1873563342 @default.
• W14568424 cites W1875561650 @default.
• W14568424 cites W1885556853 @default.
• W14568424 cites W1895115148 @default.
• W14568424 cites W1905183026 @default.
• W14568424 cites W1913457774 @default.
• W14568424 cites W1921143360 @default.
• W14568424 cites W1963545628 @default.
• W14568424 cites W1963607067 @default.
• W14568424 cites W1964312498 @default.
• W14568424 cites W1964315048 @default.
• W14568424 cites W1966398860 @default.
• W14568424 cites W1966772857 @default.
• W14568424 cites W1966828612 @default.
• W14568424 cites W1967162280 @default.
• W14568424 cites W1967194906 @default.
• W14568424 cites W1968660753 @default.
• W14568424 cites W1968972540 @default.
• W14568424 cites W1969734439 @default.
• W14568424 cites W1969806743 @default.
• W14568424 cites W1970646241 @default.
• W14568424 cites W1970683213 @default.
• W14568424 cites W1970998623 @default.
• W14568424 cites W1971162717 @default.
• W14568424 cites W1971187999 @default.
• W14568424 cites W1971571526 @default.
• W14568424 cites W1971849102 @default.
• W14568424 cites W1972011552 @default.
• W14568424 cites W1973092951 @default.
• W14568424 cites W1973794425 @default.
• W14568424 cites W1974888918 @default.
• W14568424 cites W1975500135 @default.
• W14568424 cites W1975561755 @default.
• W14568424 cites W1975730939 @default.
• W14568424 cites W1975771868 @default.
• W14568424 cites W1976552157 @default.
• W14568424 cites W1979432217 @default.
• W14568424 cites W1980214543 @default.
• W14568424 cites W1982861439 @default.
• W14568424 cites W1983438215 @default.
• W14568424 cites W1984059331 @default.
• W14568424 cites W1985931793 @default.
• W14568424 cites W1985993108 @default.
• W14568424 cites W1986538872 @default.
• W14568424 cites W1987662957 @default.
• W14568424 cites W1988109550 @default.
• W14568424 cites W1988380443 @default.
• W14568424 cites W1989183186 @default.
• W14568424 cites W1989270323 @default.
• W14568424 cites W1989483643 @default.
• W14568424 cites W1990045619 @default.
• W14568424 cites W1990803574 @default.
• W14568424 cites W1992713540 @default.
• W14568424 cites W1993487480 @default.
• W14568424 cites W1994374818 @default.
• W14568424 cites W1994471759 @default.
• W14568424 cites W1994849924 @default.
• W14568424 cites W1995434077 @default.
• W14568424 cites W1995755126 @default.
• W14568424 cites W1996303419 @default.
• W14568424 cites W1996463890 @default.
• W14568424 cites W1996527248 @default.
• W14568424 cites W1997757247 @default.
• W14568424 cites W1997801717 @default.
• W14568424 cites W1998795659 @default.
• W14568424 cites W1999705679 @default.
• W14568424 cites W2002628962 @default.
• W14568424 cites W2003702370 @default.
• W14568424 cites W2003968420 @default.
• W14568424 cites W2005868568 @default.
• W14568424 cites W2006693132 @default.
• W14568424 cites W2006833515 @default.
• W14568424 cites W2006996147 @default.
• W14568424 cites W2007124314 @default.

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