Sirtuin‐6 deficiency exacerbates diabetes‐induced impairment of wound healing

Abstract

Delayed wound healing is one of the major complications in diabetes and is characterized by chronic proinflammatory response, and abnormalities in angiogenesis and collagen deposition. Sirtuin family proteins regulate numerous pathophysiological processes, including those involved in promotion of longevity, DNA repair, glycolysis and inflammation. However the role of sirtuin 6 (SIRT6), a NAD+-dependent nuclear deacetylase, in wound healing specifically under diabetic condition remains unclear. To analyze the role of SIRT6 in cutaneous wound healing, paired 6 mm stented wound were created in diabetic db/db mice and injected siRNA against SIRT6 in the wound margins (transfection agent alone and non-sensed siRNA served as controls). Wound time to closure was assessed by digital planimetry, and wounds were harvested for histology, immunohistochemistry and Western blotting. SIRT6-siRNA treated diabetic wound showed impaired healing, which was associated with reduced capillary density (CD31 staining vessels) when compared to control treatment. Interestingly, SIRT6 deficiency decreased vascular endothelial growth factor (VEGF) expression and proliferation markers in the wounds. Furthermore, SIRT6 ablation in diabetic wound promotes nuclear factor kB (NF-kB) activation resulting in increased expression of proinflammatory markers (intercellular adhesion molecule-1, vascular cell adhesion molecule-1, tumor necrosis factor-α and interleukin-1β) and increased oxidative stress. Collectively, our findings demonstrate that loss of SIRT6 in cutaneous wound aggravates proinflammatory response by increasing NF-kB activation, oxidative stress and decrease in angiogenesis in the diabetic mice. Based on these findings, we speculate that activation of SIRT6 signaling might be a potential therapeutic approach for promoting wound healing in diabetics.

SIRT1 and SIRT6 Signaling Pathways in Cardiovascular Disease Protection

“…In line with this evidence, fibroblast cultured in low-glucose conditions shows resistance to cell senescence and enhanced SIRT6 expression by attenuating NF-jB signaling (211). Moreover, SIRT6-siRNA treateatment of cutaneous wound in diabetic mice promotes NF-jB activation and results in increased oxidative stress and proinflammatory marker expression, including ICAM-1, vascular cell adhesion molecule-1 (VCAM-1), TNF-a, and IL-1b (174).…”

MicroRNA-126 overexpression rescues diabetes-induced impairment in efferocytosis of apoptotic cardiomyocytes

“…Immunohistochemistry was performed as described previously47. In brief, paraffin-embedded tissue sections (5 μm) were deparaffinized, hydrated and washed in TBS (10 mM/l Tris HCl, 0.85% NaCl, and pH 7.5) containing 0.1% bovine serum albumin.…”

Pathogenesis of wound healing disorders in the elderly

“…Remarkably, vascular endothelial growth factor receptor (VEGFR) type 1 signaling protects from disturbed wound healing in diabetes by inhibiting the production of IL-1 β by recruited macrophages, and regulating the equilibrium between different macrophage phenotypes [ 29 ] . In addition, members of the sirtuin protein family have been shown to contribute to the wound healing process in diabetic db/db mice through regulation of oxidative stress and angiogenesis [ 30 ] .…”