Abstract 17828: Preconditioning of Mice with a Prolyl Hydroxylase Inhibitor, Dimethyloxalylglycine, Prevents Skin Flap Necrosis
Background- Local skin flaps often present with flap necrosis caused by critical disturbance of blood supply. Because hypoxia-inducible factor 1 (HIF-1) has a pivotal role in ischemic vascular responses, we assessed the hypothesis that preoperative stabilization of HIFs using prolyl hydroxylases (PHD) inhibitor contributes to improvement of skin flap survival.
Methods and Results- Mice with ischemic skin flap on the dorsum were treated with PHD inhibitor dimethyloxalylglycine (DMOG) 48hr prior to operation by intraperitoneal administration. Immunoblot assay revealed sustained up-regulation of HIF-1α protein at pre- and postoperative states in the skin. Survival area of flap and the number of CD31 positive vessels at proximal part of flaps in DMOG-treated mice were significantly increased at day seven (20.6±4.9% vs. 55.5±13.2%; P<0.001 and 11.3±1.7 vs. 17.3±3.3; P<0.05). Serum vascular endothelial growth factor (VEGF) protein at the time of operation and its receptor Flk-1 protein at proximal part of flap on day one were significantly increased in DMOG-treated mice. Furthermore, flow cytometric analysis revealed a marked induction of circulating endothelial progenitor cells (EPCs) in DMOG-treated mice on day one (0.75±0.01% vs. 1.49±0.11% of CD45 gated CD34/CD133 positive cells; P<0.005). Of interest, flow cytometric bromodeoxyuridine (BrdU)/DNA analysis showed a marked induction of proliferative progenitor cells in bone marrow 48hr after DMOG treatment. In addition, TUNEL staining at distal part of flaps revealed significantly decreasing apoptotic cells accompanied by increasing protein level of hexokinase II and decreasing Bax protein expression in DMOG-treated mice. HIF-1α heterozygous-null mice showed the reduction of flap survival areas, decreasing the number of circulating EPCs, and increasing the number of apoptotic cells, but these mutant mice with DMOG pretreatment demonstrated complete recovery of these parameters.
Conclusion- These findings indicate that prevention of flap necrosis by pretreatment of DMOG is due to enhancement of both anti-apoptotic effects and angiogenesis at the flap region via HIF-1 functions, and that pretreatment of DMOG could be a potential therapeutic strategy for prevention of flap necrosis.
- © 2011 by American Heart Association, Inc.