The Role of Snai2/Slug in Diabetes-impaired Wound Healing

Impaired wound healing is a common complication of diabetes mellitus. Advanced glycation end products (AGEs) are a consequence of diabetes and are formed from non-enzymatic reactions between glucose and proteins. The accumulation of AGEs is believed to disrupt wound repair and alter protein function. The epidermal growth factor receptor (EGFR) and a downstream effector, Snai2/Slug, are key regulators of reepithelialization, a vital component of wound healing. Reepithelialization requires keratinocyte proliferation and migration. Therefore, we examined the impact of AGEs on these EGF-stimulated responses. In this dissertation, I present evidence for a critical role of Snai2 in diabetes-impaired wound reepithelialization, extending the knowledge of Snai2 past normal wound repair. A well-studied AGE precursor, glyoxal, was used to model a diabetic environment. Glyoxal decreased EGF-stimulated EGFR activation, leading to impaired keratinocyte proliferation and migration in cell culture and in tissue explants. EGF-stimulated and basal Snai2 protein levels decreased following glyoxal treatment, and this decrease was prevented by the glycation inhibitor, aminoguanidine. Snai2 immunoprecipitated from glyoxal-exposed cells was modified by the AGE product carboxymethyl lysine, identifying Snai2 as an intracellular target of glycation. Furthermore, mice over-expressing Snai2 demonstrated enhanced epithelial outgrowth compared to wild type mice when exposed to glyoxal ex vivo. These data represent a significant breakthrough in the field of diabetes and wound healing as it is the first evidence linking Snai2 down-regulation by pathophysiologic stimuli to impairments in reepithelialization. In addition, few intracellular proteins have been identified as targets of glycation, and this work highlights Snai2 as a novel nuclear protein target with demonstrated relevance to diabetic healing. With this knowledge, we may explore methods to pharmacologically induce Snai2 protein to promote healing of diabetic wounds