Myrtenol promotes skin flap survival by inhibiting apoptosis and promoting autophagy via the MEK/ERK pathway

Skin flaps are often used for repair and reconstruction, including oral cavity and palate. However, postoperative flap necrosis limited applications. Myrtenol, a plant-derived bicyclic monoterpene, has pharmacological effects including inhibiting apoptosis and promoting autophagy. But any impact on skin flaps survival remains unclear. Thus, we established modified McFarlane flaps on 24 Sprague-Dawley rats and applied myrtenol. They were randomly divided into low-dose myrtenol (L-Myr), high-dose myrtenol (H-Myr), inhibitor and control groups. On postoperative day 7, flap survival rate was increased and Laser Doppler images showed blood circulation improvement under myrtenol treatment. Hematoxylin and eosin staining (H&E) results indicated that it increased micro vessel density (MVD) and decreased neutrophil numbers. Besides, kits detection showed that it improved anti-oxidant stress factors activities and reduced pro-oxidant stress factors contents. Moreover, immunofluorescence and Western blot results demonstrated that it upregulated the expression of pro-angiogenic factors, anti-apoptotic proteins, pro-autophagic proteins, mitogen-activated protein kinase 1/2 (MEK1/2) and extracellular signal-regulated kinases 1/2 (ERK1/2) and downregulated the expression of pro-inflammatory cytokines, pro-apoptotic proteins and anti-autophagic proteins. The specific inhibitor U0126 of MEK/ERK pathway partially reversed these effects. Overall, Myrtenol promoted angiogenesis, reduced oxidative stress, ameliorated inflammation, inhibited apoptosis and upregulated autophagy via MEK/ERK pathway to promote flap survival.