Hyperlipidemia and obesity are well known factors that inhibit wound healing. Conversely, statins, the 3- hydroxyl-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors that lower circulating cholesterol levels improve tissue repair. Recently, we have identified molecular mechanism by which statins accelerate wound healing. We found that statins promote wound healing, via blocking the synthesis of Farnesyl pyrophosphate (FPP), an important branch-point intermediate in the mevalonate pathway, essential for synthesis of sterols and isoprenylated cellular metabolites leading to cholesterol synthesis. FPP inhibits keratinocyte migration in vitro and wound healing ex vivo by acting as an anti-inflammatory agent, i.e. a bona fide agonist for glucocorticoid receptor (GR), whereas statins reverse this effect. Therefore, we hypothesize that statins may accelerate wound healing by modulating the inflammatory response. This hypothesis will be tested using topical statins on hyperlipidemic and healthy (normolipidemic) porcine wound healing model in vivo. Once an optimal topical dose of statins is determined (Aim 1) we will determine the effects of statins on the inflammatory response by measuring levels of pro- and anti-inflammatory cytokines, GR- phosphorylation as well as neutrophil and macrophage infiltration in hyperlipidemic and normolipidemic porcine wound model (Aim 2A). Recently, statins were found to have anti-microbial effect. Bacterial infection is one of the most common complications of wound healing, known to inhibit this process. Thus, we will also test if topical statins alone or in combination with systemic statins, accelerate wound healing of bacterially-infected wounds (Aim 2B). The high impact of proposed study is multi-factorial: 1) it will provide a validated in vivo experimental models to study cutaneous wound healing and infection related to obesity and high cholesterol levels;2) develop pre- clinical evidence for potential topical use of statins to treat wound healing disorders and 3) provide new insights into the mechanism by which statins may impact healing ability of wounds in patients who are using them systemically.

Public Health Relevance

Number of patients (particularly elderly, obese and/or diabetic) are currently treated by various modulators of cholesterol synthesis, statins, which may impact their ability to heal wounds. This study will provide a better understanding of the pleiotropic effects of statins as well as the mechanisms by which they modulate inflammatory response and accelerate wound healing in vivo, in the presence of high-cholesterol and/or wound infection, which may provide novel therapeutic approach for treatment of wound healing disorders.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Exploratory/Developmental Grants (R21)
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Special Emphasis Panel (ZRG1-MOSS-G (02))
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Tseng, Hung H
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University of Miami School of Medicine
Schools of Medicine
Coral Gables
United States
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Sawaya, Andrew P; Pastar, Irena; Stojadinovic, Olivera et al. (2018) 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 293:1439-1449
Pastar, Irena; Stojadinovic, Olivera; Sawaya, Andrew P et al. (2016) Skin Metabolite, Farnesyl Pyrophosphate, Regulates Epidermal Response to Inflammation, Oxidative Stress, and Migration. J Cell Physiol 231:2452-63
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