Connexins: a new therapeutic target for diabetic wound healing

Research output: Contribution to conferencePaper

Abstract

Non-healing cutaneous wounds such as leg ulcers are a major cause of morbidity and mortality, especially in diabetes. Currently 67% of ulcers fail to respond to treatment after 20 weeks of care, and are a substantial time and cost burden. Recent studies suggest significant increases in skin wound healing rates occur by reduction of connexin (Cx) mediated communication (CMC). Connexins thus offer a new therapeutic target for wound care. We analysed the effects of Gap27, a connexin mimetic peptide that reduces CMC, on CMC and cell migration in human dermal fibroblasts cultured in normal or diabetic levels of glucose and insulin, and consequent alterations of expression of cell motility genes.
Cells were treated with 5.5 mM glucose and 1 nM insulin (‘normal’) or 25 mM glucose and 10 nM insulin (‘high’). Individual migrating fibroblasts were injected with fluorescent dyes and dye spread monitored. Migration studies examined rates of scrape-wound closure in fibroblasts in normal or high conditions with or without 100 µM Gap27. Migrating fibroblasts were cultured in normal or high glucose levels, treated with Gap27 or scrambled peptide (control), and mRNA was subjected to PCR array analysis.
Cells in high glucose and insulin showed reduced CMC compared to those in normal levels as indicated by reduced dye transfer. Gap27 significantly increased cell migration rates of fibroblasts in both normal and high glucose and insulin. In euglycaemic migrating fibroblasts, Gap27 upregulated thirty-four genes and downregulated 1 gene involved in the extra-cellular matrix (ECM) and cell adhesion pathway. By contrast, under hyperglycaemia, Gap27 upregulated one gene and downregulated 9 genes.
Gap27 blocked CMC and increased cell migration rates in both normal and high levels of glucose and insulin. Gap27 may have different modes of action in normal and diabetic conditions, as genes associated with ECM remodelling were upregulated in euglycaemia, and genes associated with producing ECM components were down-regulated in hyperglycaemia. Connexin mimetic peptides improve skin cell migration in ‘diabetic’ conditions in vitro and have therapeutic potential in healing chronic wounds.
Original languageEnglish
Publication statusPublished - 2010

Keywords

  • connexin
  • wound healing

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