Detrimental effect of Hypoxia-inducible factor-1α-induced autophagy on multiterritory perforator flap survival in rats

Hypoxia-inducible factor-1α (HIF-1α) plays a key role in angiogenesis, improves flap survival, and activates autophagy. The effect of HIF-1α-induced autophagy is still debatable. Thus, we investigated the effect of HIF-1α-induced autophagy on multiterritory perforator flap survival. In this study, 99 male Sprague-Dawley rats received multiterritory perforator flap procedure and were divided into three groups with 33 each. The dimethyloxalylglycine (DMOG) plus 3-methyladenine (3-MA) group received intraperitoneal injection of DMOG (40 mg/kg) and 3-MA (10 mg/kg). The DMOG group and control group received comparative DMOG and saline respectively. On postoperative day (POD) 7, HIF-1α’s activities of flap survival and perfusion improvement were confirmed in DMOG group, however, its positive effects were further enhanced by co-administration of autophagy inhibitor, 3-MA. On POD 1, vascular endothelial growth factor, mean microvascular density and blood perfusion were not affected by HIF-1α up-regulation or autophagy inactivation. However, HIF-1α-induced autophagy augments apoptosis and oxidative stress. The increased level of apoptosis and oxidative stress was reversed by 3-MA and resulted in further flap survival improvement. In conclusion, HIF-1α-induced autophagy has a detrimental effect on multiterritory perforator flap survival and the flap survival was determined by the combined effects of ischemia and reperfusion injury.