“Protective effect of KUS121, a valosin-containing protein (VCP) modulator, against ischemia/reperfusion injury in axial pattern flaps”

BACKGROUND: Kyoto University Substance (KUS) 121 is a novel modulator of valosin-containing protein (VCP), with reported protective effects against ischemia/reperfusion (I/R) injury across various organs. This study evaluated the therapeutic effect of KUS121 on axial pattern flaps subjected to I/R injury. METHODS: Axial pattern flaps nourished by superficial epigastric vessels were created in Sprague-Dawley rats, measuring 3 × 6 cm, and subjected to 8 hours of ischemia followed by reperfusion. KUS121 (100 mg/kg) was administered intraperitoneally 1 hour before flap elevation (KUS121-pretreated group) or immediately after reperfusion (KUS121-posttreated group), followed by once-daily administration from postoperative day 1 to 6. The control group received no KUS121. Flap survival was evaluated macroscopically on day 7. Histological and immunohistochemical evaluations were performed on day 3 in the KUS121-pretreated and control groups. RESULTS: Flap survival was significantly higher in the KUS121-pretreated group (80.7±7.8%) and KUS121-posttreated group (96.2±1.1%) than in the control group (48.8±5.3%; p=0.002 and p<0.001, respectively). On day 3, TdT-mediated dUTP-biotin nick-end labeling (TUNEL)-positive cells were significantly decreased in the KUS121-pretreated group compared to the control group in the distal flap region (2.3±0.5 vs. 7.7±1.1 cells/field; p<0.001) and in the middle region (2.3±0.4 vs. 9.0±1.1 cells/field; p<0.001). C/EBP homologous protein (CHOP)-positive cells were also significantly decreased in the KUS121-pretreated group compared with controls in the distal (9.0±1.5 vs. 21.4±1.8 cells/field; p<0.001) and middle (6.8±0.8 vs. 23.5±2.9 cells/field; p<0.001) regions. CONCLUSIONS: KUS121 markedly improves axial pattern flap survival by attenuating I/R-induced apoptosis and endoplasmic reticulum stress.