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Topical mevastatin promotes wound healing by inhibiting the transcription factor c-Myc via the glucocorticoid receptor and the long non-coding RNA Gas5.
J Biol Chem. 2018 01 26; 293(4):1439-1449.JB

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.

Authors+Show Affiliations

From the Molecular and Cellular Pharmacology Program and. Wound Healing and Regenerative Medicine Research Program, Department of Dermatology and Cutaneous Surgery, University of Miami Miller School of Medicine, Miami, Florida 33136.Wound Healing and Regenerative Medicine Research Program, Department of Dermatology and Cutaneous Surgery, University of Miami Miller School of Medicine, Miami, Florida 33136.Wound Healing and Regenerative Medicine Research Program, Department of Dermatology and Cutaneous Surgery, University of Miami Miller School of Medicine, Miami, Florida 33136. the Immunology, Infection, and Inflammation Graduate Program, Faculty of Medical Sciences, University of Kragujevac, 34000 Kragujevac, Serbia, and.Wound Healing and Regenerative Medicine Research Program, Department of Dermatology and Cutaneous Surgery, University of Miami Miller School of Medicine, Miami, Florida 33136.Wound Healing and Regenerative Medicine Research Program, Department of Dermatology and Cutaneous Surgery, University of Miami Miller School of Medicine, Miami, Florida 33136.Wound Healing and Regenerative Medicine Research Program, Department of Dermatology and Cutaneous Surgery, University of Miami Miller School of Medicine, Miami, Florida 33136.Wound Healing and Regenerative Medicine Research Program, Department of Dermatology and Cutaneous Surgery, University of Miami Miller School of Medicine, Miami, Florida 33136. the Wound Healing Clinical Research Program, University of Miami Hospital, University of Miami Health System, Miami, Florida 33136.From the Molecular and Cellular Pharmacology Program and mtcanic@med.miami.edu. Wound Healing and Regenerative Medicine Research Program, Department of Dermatology and Cutaneous Surgery, University of Miami Miller School of Medicine, Miami, Florida 33136. the Wound Healing Clinical Research Program, University of Miami Hospital, University of Miami Health System, Miami, Florida 33136.

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

29158265

Citation

Sawaya, Andrew P., et al. "Topical Mevastatin Promotes Wound Healing By Inhibiting the Transcription Factor c-Myc Via the Glucocorticoid Receptor and the Long Non-coding RNA Gas5." The Journal of Biological Chemistry, vol. 293, no. 4, 2018, pp. 1439-1449.
Sawaya AP, Pastar I, Stojadinovic O, et al. Topical mevastatin promotes wound healing by inhibiting the transcription factor c-Myc via the glucocorticoid receptor and the long non-coding RNA Gas5. J Biol Chem. 2018;293(4):1439-1449.
Sawaya, A. P., Pastar, I., Stojadinovic, O., Lazovic, S., Davis, S. C., Gil, J., Kirsner, R. S., & Tomic-Canic, M. (2018). Topical mevastatin promotes wound healing by inhibiting the transcription factor c-Myc via the glucocorticoid receptor and the long non-coding RNA Gas5. The Journal of Biological Chemistry, 293(4), 1439-1449. https://doi.org/10.1074/jbc.M117.811240
Sawaya AP, et al. Topical Mevastatin Promotes Wound Healing By Inhibiting the Transcription Factor c-Myc Via the Glucocorticoid Receptor and the Long Non-coding RNA Gas5. J Biol Chem. 2018 01 26;293(4):1439-1449. PubMed PMID: 29158265.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Topical mevastatin promotes wound healing by inhibiting the transcription factor c-Myc via the glucocorticoid receptor and the long non-coding RNA Gas5. AU - Sawaya,Andrew P, AU - Pastar,Irena, AU - Stojadinovic,Olivera, AU - Lazovic,Sonja, AU - Davis,Stephen C, AU - Gil,Joel, AU - Kirsner,Robert S, AU - Tomic-Canic,Marjana, Y1 - 2017/11/20/ PY - 2017/08/29/received PY - 2017/11/10/revised PY - 2017/11/22/pubmed PY - 2018/11/28/medline PY - 2017/11/22/entrez KW - Gas5 KW - Myc (c-Myc) KW - diabetic foot ulcers KW - glucocorticoid receptor KW - long noncoding RNA (long ncRNA, lncRNA) KW - skin KW - statin KW - wound healing SP - 1439 EP - 1449 JF - The Journal of biological chemistry JO - J Biol Chem VL - 293 IS - 4 N2 - 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. SN - 1083-351X UR - https://www.unboundmedicine.com/medline/citation/29158265/Topical_mevastatin_promotes_wound_healing_by_inhibiting_the_transcription_factor_c_Myc_via_the_glucocorticoid_receptor_and_the_long_non_coding_RNA_Gas5_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0021-9258(20)39143-2 DB - PRIME DP - Unbound Medicine ER -