Inhibition of ANGPT2 activates autophagy during hypertrophic scar formation via PI3K/AKT/mTOR pathway

作者：Chen, Hongxin; Xu, Kai; Sun, Chao; Gui, Si; Wu, Juanjuan; Wang, Song^*

来源：ANAIS BRASILEIROS DE DERMATOLOGIA, 2023, 98(1): 26-35.

DOI：10.1016/j.abd.2021.12.005

• Autophagy
• Angiopoietin-2
• Cell proliferation
• Cicatrix
• hypertrophic
• Class II phosphatidylinositol 3-kinases
• Extracellular matrix
• Fibroblast

Background: Hypertrophic scar (HS), a fibroproliferative disorder caused by aberrant wound healing following skin injuries such as burns, lacerations and surgery, is characterized by inva-sive proliferation of fibroblasts and excessive extracellular matrix (ECM) accumulation. The dysregulation of autophagy is the pathological basis of HS formation. Previously, angiopoietin-2 (ANGPT2) was found to be overexpressed in HS fibroblasts (HSFs) compared with normal skin @@@ fibroblasts. However, whether ANGPT2 participates in the process of HS formation and the potential molecular mechanisms are not clear. @@@ Objective: This study is intended to figure out the role of ANGPT2 and ANGPT2-mediated autophagy during the development of HS. @@@ Methods: RT-qPCR was used to detect ANGPT2 expression in HS tissues and HSFs. HSFs were transfected with sh-ANGPT2 to knock down ANGPT2 expression and then treated with MHT1485, the mTOR agonist. The effects of sh-ANGPT2 or MHT1485 on the proliferation, migration, autophagy and ECM accumulation of HSFs were evaluated by CCK-8 assay, Transwell assay and western blotting. The expression of PI3K/Akt/mTOR pathway-related molecules (p-PI3K, p-Akt and p-mTOR) was assessed by western blotting. @@@ Results: ANGPT2 expression was markedly upregulated in HS tissues and HSFs. ANGPT2 knock -down decreased the expression of p-PI3K, p-Akt and p-mTOR. ANGPT2 knockdown activated autophagy and inhibited the proliferation, migration, and ECM accumulation of HSFs. Addition-ally, the treatment of MHT1485, the mTOR agonist, on ANGPT2-downregulated HSFs, partially reversed the influence of ANGPT2 knockdown on HSFs. @@@ Study limitations: The study lacks the establishment of more stable in vivo animal models of HS for investigating the effects of ANGPT2 on HS formation in experimental animals. @@@ Conclusions: ANGPT2 downregulation represses growth, migration, and ECM accumulation of HSFs via autophagy activation by suppressing the PI3K/Akt/mTOR pathway. Our study provides a novel potential therapeutic target for HS.