Alda-1, an Aldehyde Dehydrogenase 2 Agonist, Improves Cutaneous Wound Healing by Activating Epidermal Keratinocytes via Akt/GSK-3β/β-Catenin Pathway

Background The cutaneous wound healing process mainly comprises re-epithelialization, fibrosis, and neovascularization. Impaired wound healing is common but tricky in plastic surgery. Aldehyde dehydrogenase 2 (ALDH2), the most effective subset of the ALDH enzyme family, is known to exert a major role in detoxification of aldehydes. Activation of ALDH2 by Alda-1 (a specific agonist) has been found to protect against cardiovascular diseases. However, no research has paid attention to the potential of ALDH2 activation in regulating wound healing. The previous studies suggested a high expression of ALDH2 in normal skin tissue. The aim of this study was to investigate if Alda-1 may ameliorate wound healing. Methods A full-thickness excisional wound model was established in vivo. Adult male C57BL/6 mice were randomly divided into DMSO and Alda-1 groups. Mice received an intraperitoneal injection of DMSO or 10 mg/mL Alda-1 (10 mg/kg body weight, dissolved in DMSO) for 7 days. The wound healing rate was measured at 0, 3, 5, and 7 days. Distribution of ALDH2 in wound tissue was showed. ALDH2 enzymatic activity was examined at 3, 5, and 7 days. The elongation of epithelial tongue was detected by hematoxylin-eosin staining, and collagen deposition was analyzed by Masson's trichrome staining at 7 days. Expressions of alpha-smooth muscle actin (alpha-SMA), transforming growth factor beta (TGF-beta), CD31, collagen 1, collagen 3, and elastin were stained by immunohistochemistry at 5 and 7 days. The HaCaT cell line was applied in vitro. Proliferation and migration were tested using CCK8 and wound healing assay separately. The level of TGF-beta was examined by ELISA. Protein levels of the Akt/glycogen synthase kinase-3 beta (GSK-3 beta)/beta-catenin pathway were determined by western blotting. Results Alda-1 accelerated wound healing rates. ALDH2 activity in wound sites was restored. Alda-1 promoted the length of the epithelial tongue, collagen deposition, as well as expressions of alpha-SMA, TGF-beta, collagen 1/3, elastin, but did not affect CD31. Proliferation, migration, and TGF-beta secretion were promoted by Alda-1 and deregulated by CVT-10216 (an ALDH2 inhibitor). Protein variations of the Akt/GSK-3 beta/beta-catenin pathway were found to accord with ALDH2 changes. Conclusions Alda-1, an ALDH2 agonist, improves cutaneous wound healing in a full-thickness excisional wound model. Alda-1 activates proliferation, migration, and TGF-beta secretion of HaCaT (epidermal keratinocytes) by regulating the Akt/GSK-3 beta/beta-catenin pathway. No Level Assigned This journal requires that authors assign a level of evidence to each submission to which Evidence-Based Medicine rankings are applicable. This excludes Review Articles, Book Reviews, and manuscripts that concern Basic Science, Animal Studies, Cadaver Studies, and Experimental Studies. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266.