Simvastatin Improves Incisional Wound Healing in a Rat Model: An Experimental Study
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Index: WOUNDS. 2012;24(7):195–200.
Abstract: This study investigated the effect of simvastatin on the healing process of abdominal wall wounds in rats. Methods. The study was performed with adult female Wistar-Albino rats. Control group (n = 20) rats were fed standard laboratory diet until 12 hours before surgery. Study group (n = 20) rats received oral simvastatin therapy with an orogastric tube (10 mg/kg once a day) for 7 days until 12 hours before surgery. Each rat was anesthetized, and a 4 cm-long midline laparotomy was performed. Ten animals from each group were killed at postoperative days (PODs) 7 and 14. Breaking strength analysis was measured, and the abdominal incision wounds were examined histologically. Results. Hydroxyproline levels and tensile strength of abdominal fascia were significantly higher in the study group on PODs 7 and 14 compared to the control group. The granulation tissue fibroblast maturation scores on POD 7, and both collagen deposition scores and neovascularization scores on PODs 7 and 14, were found to be statistically significantly higher in the simvastatin treatment group compared to the control group, based on the results of the histologic tissue examinations. Conclusion. Simvastatin can be used as a supporting therapy in wound healing.
Wound healing is a natural restorative response to tissue injury. It is a complex and dynamic process with reconstitution and restoration of the tensile strength of injured skin or tissue. Wound healing involves a well-coordinated, highly regulated series of events, including inflammation, tissue formation, revascularization, and tissue remodeling.1,2 The important role played by nitric oxide (NO) on wound healing has recently been explored.1,3,4 The upregulation of NO has a positive influence on wound healing at multiple levels, including angiogenesis, inflammation, endothelial and epithelial cell proliferation, matrix deposition, and remodeling.1,5 Reduced NO production in wounds has been shown to be associated with impaired healing and to coincide with reduced collagen deposition.5,6
Statins are known to decrease cholesterol levels, which results in a substantial reduction of cardiovascular mortality in patients with hypercholesterolaemia. Statins reduce cholesterol levels by inhibiting the enzyme 3-hydroxy-3-methylglutaryl-coenzyme A (HMGCoA) reductase, which converts HMG-CoA to mevalonate, the precursor of cholesterol.7,8 In animal studies, the use of statins on the vascular system, such as the coronary artery, cerebral artery, small mesenteric artery, aorta, and corpus cavernosum, was shown to result in vascular relaxation by upregulating NO synthase.9,10 Statins have been shown to up-regulate endothelial NO synthase (eNOS) production and subsequent NO bioavailability; this now is believed to be their main mechanism of action.11 In addition to reducing lipid levels, these agents can improve endothelial function and reduce oxidative stress, which can improve microvascular function.8–10 Simvastatin, one of the most common statins, has been demonstrated to be able to augment the secretion of vascular endothelial growth factor (VEGF) in different cell types and increase NO products in wounds, which can be a power stimulator of angiogenesis.6 Matsuno et al12 showed that simvastatin regulates endothelial regeneration by an over-release of VEGF resulting in a prompt endothelial healing after vascular injury. Recently, Cakmak et al13 reported that administration of simvastatin therapy had positive effects on the healing of colonic anastomoses. To the authors’ knowledge, the effects of simvastatin in an experimental model of incisional wound healing has not yet been investigated.