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

Abstract

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. 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 10mg/mL Alda-1 (10mg/kg body weight, dissolved in DMSO) for 7days. The wound healing rate was measured at 0, 3, 5, and 7days. Distribution of ALDH2 in wound tissue was showed. ALDH2 enzymatic activity was examined at 3, 5, and 7days. The elongation of epithelial tongue was detected by hematoxylin-eosin staining, and collagen deposition was analyzed by Masson's trichrome staining at 7days. 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 7days. The HaCaT cell line was applied in vitro. Proliferation and migration were tested using CCK8 and wound healing assay separately. The level of TGF-β 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. 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-β secretion were promoted by Alda-1 and deregulated by CVT-10216 (an ALDH2 inhibitor). Protein variations of the Akt/GSK-3β/β-catenin pathway were found to accord with ALDH2 changes. Alda-1, an ALDH2 agonist, improves cutaneous wound healing in a full-thickness excisional wound model. Alda-1 activates proliferation, migration, and TGF-β secretion of HaCaT (epidermal keratinocytes) by regulating the Akt/GSK-3β/β-catenin pathway. 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.