Mevastatin For Topical Use In Diabetic Foot Ulcers To Accelerate Wound Closure By Inhibition Of Caveolin-1 And Restoration Of Egf Signaling
Andjela N. Egger, Andrew P. Sawaya, Ivan Jozic, Rivka C. Stone, Irena Pastar, Marjana Tomic-Canic.
Wound Healing and Regenerative Medicine Research Program, Dr. Phillip Frost Department of Dermatology and Cutaneous Surgery, University of Miami Miller School of Medicine, Miami, FL, USA.
BACKGROUND: Diabetic foot ulcers (DFUs) are a type of chronic wound characterized by a hyperproliferative and non-migratory epidermis. Current treatment modalities are limited and frequently ineffective, thereby increasing the demand for more innovative therapies. We have shown that epidermal growth factor receptor (EGFR) is mislocalized to the cytoplasm and downregulated in the epidermis from DFU patients, whereas Caveolin-1 (Cav1), a structural membrane protein, is overexpressed in DFUs, suggesting that Cav1 may act to inhibit and sequester EGFR to inhibit wound healing.
METHODS: To evaluate the ability of topical statins to promote healing through Cav1 suppression and EGF restoration, we collected tissue samples from patients with DFUs. Next, we treated DFUs ex vivoand porcine in vivowounds with topical Mevastatin (MEV), performed histology validations and protein assessments focusing on localization and expression of Cav1 and activation of EGFR. Effects of MEV on cellular proliferation and migration were evaluated using in vitroassays with primary human keratinocytes.
RESULTS: DFU histology confirmed hyperproliferative epidermis and thickened cornified layer. Compared to vehicle-treated controls, MEV inhibited Cav1 and activated p-EGFR in MEV-treated DFUs. Immunoperoxidase staining of in vivoporcine wounds showed MEV decreased Cav1 expression and enhanced epithelization compared to controls.
CONCLUSIONS: These findings suggest that topical application of MEV in DFUs can be used to promote wound closure by inhibiting Cav1 and restoring EGF signaling otherwise downregulated in DFUs. Recombinant EGF therapy failed to reach FDA efficacy in clinical trials for treatment of chronic wounds. Our findings offer possible explanation as to why: due to sequestration of EGFR and inhibition of its signaling by Cav1. Further, our results highlight the possibility of repurposing statins for topical use in chronic wounds to reverse Cav1-mediated inhibition to facilitate EGF signaling and wound closure.
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