Inhibition of histone deacetylases accelerates wound healing in diabetic skin and is associated with vascularization and epidermal tight junction protein expression.

Abstract

Background: Chronic wounds in diabetic patients, represent a significant clinical challenge due to impaired epidermal barrier function and deficient wound healing. The development of novel therapeutic strategies aimed at enhancing both barrier integrity and wound healing is therefore critical. Recent evidence suggests that histone deacetylase inhibitors (iHDACs) may modulate wound healing.

Objective: This study aimed to evaluate the effect of iHDACs, 1,3-Diphenylurea (DiPU), 2'-Aminoacetanilide (Ace), and Tert-butyl (2-aminophenyl) carbamate (N-boc), on epidermal barrier integrity and tight junction (TJ) protein expression, as well as their ability to promote wound healing and vascularization under diabetes conditions.

Methods: Diabetes was induced in mice by streptozotocin (STZ) administration. Full-thickness excisional wounds were created, and wound closure was quantified by digital planimetry. Tissue samples were analyzed by H&E and Masson's trichrome staining to assess histological changes and collagen deposition. claudin-1, ZO-1, and occludin were evaluated by immunohistochemistry. Vascularization was quantified by measuring microvessel density.

Results: Treatment with iHDACs improved re-epithelialization and increased the expression of tight junction proteins, suggesting restoration of molecular components associated with epidermal barrier integrity. Moreover, all treatments promoted wound closure. Macroscopic observations and quantitative analyses further demonstrated that N-boc and Ace significantly enhanced the formation of denser and more organized vascular networks in both healthy and diabetic mice, whereas DiPU produced a more moderate pro-angiogenic response in diabetic wounds.

Conclusion: These findings indicate that iHDACs may offer therapeutic benefit by reinforcing epidermal barrier function and stimulating wound healing and vascularization, supporting their potential use as treatments for chronic wounds.