Activation of aldehyde dehydrogenase-2 improves ischemic random skin flap survival in rats

• DOI: 10.3389/fimmu.2023.1127610
• Publication Date: 2023-06-27T07:04:54Z
• Authors: Taotao Zhou; Xibin Wang; Kaitao Wang; Yi Lin; Zhefeng Meng; Qicheng Lan; Zhikai Jiang; Jianpeng Chen; Yuting Lin; Xuao Liu; Hang Lin; Shijie Wu; Dingsheng Lin
• Keywords: Malondialdehyde

Objective Random skin flaps have many applications in plastic and reconstructive surgeries. However, distal flap necrosis restricts wider clinical utility. Mitophagy, a vital form of autophagy for damaged mitochondria, is excessively activated ischemia/reperfusion (I/R) injury, thus inducing cell death. Aldehyde dehydrogenase-2 (ALDH2), an allosteric tetrameric enzyme, plays important role regulating mitophagy. We explored whether ALDH2 by N-(1,3-benzodioxol-5-ylmethyl)-2,6-dichlorobenzamide (Alda-1) could reduce the risk ischemic random necrosis, possible mechanism action. Methods Modified McFarlane models were established 36 male Sprague-Dawley rats assigned randomly to three groups: low-dose Alda-1 group (10 mg/kg/day), high-dose (20 mg/kg/day) control group. The percentage surviving area, neutrophil density microvessel (MVD) evaluated on day 7. Oxidative stress was quantitated measuring superoxide dismutase (SOD) malondialdehyde (MDA) levels. Blood perfusion angiogenesis assessed via laser Doppler flow imaging lead oxide-gelatin angiography, respectively. expression levels inflammatory cytokines (IL-1β, IL-6, TNF-α), vascular endothelial growth factor (VEGF), ALDH2, PTEN-induced kinase 1 (PINK1), E3 ubiquitin ligase (Parkin) immunohistochemically detected. Indicators mitophagy such as Beclin-1, p62, microtubule-associated protein light chain 3 (LC3) immunofluorescence. Results significantly enhanced survival area flaps. SOD activity increased MDA level decreased, suggesting that reduced oxidative stress. upregulated, mitophagy-related proteins (PINK1, Parkin, LC3) downregulated, indicating inhibited through PINK1/Parkin signaling pathway. Treatment with infiltration expressions cytokines. upregulated VEGF expression, MVD, promoted angiogenesis, blood perfusion. Conclusion activation can effectively enhance viability inhibiting PINK1/Parkin-dependent Moreover, enhancement also exerts anti-inflammatory angiogenic properties.