Topical mevastatin promotes wound healing by inhibiting the transcription factor c-Myc via the glucocorticoid receptor and the long non-coding RNA Gas5

Andrew P. Sawaya, Irena Pastar, Olivera Stojadinovic, Sonja Lazovic, Stephen C Davis, Joel Gil Rodriguez, Robert Kirsner, Marjana Tomic-Canic

Research output: Contribution to journalArticle

7 Citations (Scopus)

Abstract

Diabetic foot ulcers (DFUs), a life-threatening complication of diabetes mellitus, have limited treatment options, often resulting in amputations. HMG-CoA reductase inhibitors such as statins are cholesterol-reducing agents that may provide a new therapeutic option. Statins target the cholesterol pathway and block the synthesis of the wound-healing inhibitors farnesyl pyrophosphate (FPP) and cortisol, ligands for the glucocorticoid receptor (GR). Here we demonstrate that the naturally occurring statin mevastatin reverses FPP's effects and promotes healing by using in vitro wound healing assays, human ex vivo and porcine in vivo wound models, and DFU tissue. Moreover, we measured cortisol levels by ELISA and found that mevastatin inhibited cortisol synthesis in keratinocytes and biopsies from patients with DFU. Of note, topical mevastatin stimulated epithelialization and angiogenesis in vivo. Mevastatin also reversed FPP-mediated induction of the GR target, the transcription factor c-Myc (a biomarker of non-healing wounds), in porcine and human wound models. Importantly, mevastatin reversed c-Myc overexpression in DFUs. It induced expression of the long noncoding RNA Gas5 that blocks c-Myc expression, which was confirmed by overexpression studies. We conclude that topical mevastatin accelerates wound closure by promoting epithelialization via multiple mechanisms: Modulation of GR ligands and induction of the long noncoding RNA Gas5, leading to c-Myc inhibition. In light of these findings, we propose that repurposing statin drugs for topical treatment of DFUs may offer another option for managing this serious condition.

Original languageEnglish (US)
Pages (from-to)1439-1449
Number of pages11
JournalJournal of Biological Chemistry
Volume293
Issue number4
DOIs
StatePublished - Jan 1 2018

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Long Noncoding RNA
Glucocorticoid Receptors
Hydroxymethylglutaryl-CoA Reductase Inhibitors
Diabetic Foot
Wound Healing
Transcription Factors
Hydrocortisone
Wounds and Injuries
Swine
Drug Repositioning
Cholesterol
Ligands
Biopsy
Reducing Agents
Biomarkers
Diabetes Complications
Medical problems
Keratinocytes
Amputation
mevastatin

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Topical mevastatin promotes wound healing by inhibiting the transcription factor c-Myc via the glucocorticoid receptor and the long non-coding RNA Gas5. / Sawaya, Andrew P.; Pastar, Irena; Stojadinovic, Olivera; Lazovic, Sonja; Davis, Stephen C; Gil Rodriguez, Joel; Kirsner, Robert; Tomic-Canic, Marjana.

In: Journal of Biological Chemistry, Vol. 293, No. 4, 01.01.2018, p. 1439-1449.

Research output: Contribution to journalArticle

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