Next Generation Sequencing Reveals Novel Mechanism Of Statin Action To Promote Healing In Pre-clinical And Clinical Models
Andrew Sawaya, Irena Pastar, Ivan Jozic, Olivera Stojadinovic, Stephen C. Davis, Joel Gill, Robert S. Kirsner, Marjana Tomic-Canic.
Wound Healing and Regenerative Medicine Research Program, Department of Dermatology and Cutaneous Surgery, University of Miami Miller School of Medicine, Miami, FL, USA.
Statins, HMG-CoA reductase inhibitors, primarily used as cholesterol reducing agents, represent a promising new therapeutic modality for treatment of non-healing wounds. We show that statins promote epithelialization in vivo and ex vivo using porcine and human ex vivo wound models. To reveal molecular mechanisms of action we performed next generation sequencing of mevastatin-treated primary human keratinocytes. RNA-seq analysis followed by functional confirmation revealed that mevastatin induced cell migration while inhibited cell proliferation, suggesting that statins may shift the chronic wounds from a hyper-proliferative to a migratory phenotype to promote healing. Ingenuity pathway analyses identified the epidermal growth factor receptor (EGFR) signaling as the major pathway modulated by mevastatin. We confirmed that mevastatin blocked keratinocyte proliferation by inhibiting expression of cell cycle genes while promoting EGF-induced keratinocyte migration. More importantly, we found mevastatin restored EGF signaling cascade in diabetic foot ulcer tissue, suggesting statins can re-sensitize patients to EGF stimulation. Furthermore, we found that mevastatin inhibited cortisol synthesis, a potent inhibitor of keratinocyte migration and epithelialization, and its downstream target c-myc, a biomarker for non-healing wound tissue and major activator of hyper-proliferation. This inhibition occurred through statin-induced expression of the long non-coding RNA, Gas5. We conclude that mevastatin promotes wound healing through multiple complex mechanisms including restoring EGFR and suppressing cortisol pathway, and through regulating molecular activators and inhibitors of wound healing to facilitate therapeutic reprogramming.
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