A Connexin43 Mimetic Peptide Promotes Regenerative Healing and Improves Mechanical Properties in Skin and Heart

Significance: Evidence is building that the gap junction protein connexin43 (Cx43) is an important molecule in regenerative healing of skin and heart. Excess scarring from skin wound healing is a continuing clinical problem. Humans generally lack the ability to regenerate tissue following injury, and some degree of fibrotic repair occurs. In the skin, this results in unsightly scars with inferior mechanical properties. In the heart, scarring causes disruption in the contractility of cardiac muscle and increases the risk of deadly arrhythmia. Therapies that tip the balance of wound healing away from scar tissue and toward regeneration would thus represent a significant medical advance. Recent Advances: A cell-permeant peptide, alpha CT1 (alpha connexin carboxyl-terminal peptide), based on the carboxyl-terminus of connexin43, has been shown to elicit changes in gap junction organization and intracellular communication. In the skin, alpha CT1 applied at acute time points results in decreased inflammatory response, reduced area of scar progenitor tissue, and restoration of more normal dermal structure and mechanical strength. alpha CT1 application to infarcted hearts improved cardiac contractility, reduced the propensity for arrhythmia, and increased conduction velocity through the injured heart. Critical Issues: Application of therapies like alpha CT1 could reduce cutaneous scarring and improve mechanical properties of healed skin and the contractile function and electrical stability of the heart following injury or surgery. Future Directions: alpha CT1 is a potential therapy for cutaneous wounds that could lead to reduced scarring and improvements in the mechanical properties of healed skin. For injured myocardial tissues, this Cx43 mimetic peptide may also provide a therapeutic approach for targeting pathological fibrosis and reducing the likelihood of sudden death from cardiac arrhythmias.