title: 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 analyse the role of SIRT6 in cutaneous wound healing, paired 6-mm stented wound was created in diabetic db/db mice and injected siRNA against SIRT6 in the wound margins (transfection agent alone and nonsense 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 expression and proliferation markers in the wounds. Furthermore, SIRT6 ablation in diabetic wound promotes nuclear factor-κB (NF-κB) 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-κB activation, oxidative stress and decrease in angiogenesis in the diabetic mice. Based on these findings, we speculate that the activation of SIRT6 signalling might be a potential therapeutic approach for promoting wound healing in diabetics.
authors.affiliation: Department of Cardiovascular Sciences, Center for Cardiovascular Regeneration, Houston Methodist Research Institute, Houston, TX, USA.
authors.forename: Rajarajan A
authors.initials: RA
authors.lastname: Thandavarayan
authors.affiliation: Center for Translational Medicine, Temple University School of Medicine, Philadelphia, PA, USA.
authors.forename: Venkata Naga Srikanth
authors.initials: VN
authors.lastname: Garikipati
authors.affiliation: Department of Cardiovascular Sciences, Center for Cardiovascular Regeneration, Houston Methodist Research Institute, Houston, TX, USA.
authors.forename: Darukeshwara
authors.initials: D
authors.lastname: Joladarashi
authors.affiliation: Department of Cardiovascular Sciences, Center for Cardiovascular Regeneration, Houston Methodist Research Institute, Houston, TX, USA.
authors.forename: Sahana
authors.initials: S
authors.lastname: Suresh Babu
authors.affiliation: Department of Cardiovascular Sciences, Center for Cardiovascular Regeneration, Houston Methodist Research Institute, Houston, TX, USA.
authors.forename: Prince
authors.initials: P
authors.lastname: Jeyabal
authors.affiliation: Center for Translational Medicine, Temple University School of Medicine, Philadelphia, PA, USA.
authors.forename: Suresh K
authors.initials: SK
authors.lastname: Verma
authors.affiliation: Feinberg Cardiovascular Research Institute, Northwestern University, Chicago, IL, USA.
authors.forename: Alexander R
authors.initials: AR
authors.lastname: Mackie
authors.affiliation: Center for Translational Medicine, Temple University School of Medicine, Philadelphia, PA, USA.
authors.forename: Mohsin
authors.initials: M
authors.lastname: Khan
authors.affiliation: Department of Clinical Pharmacology, Niigata University of Pharmacy and Applied Life Sciences, Niigata, Japan.
authors.forename: Somasundaram
authors.initials: S
authors.lastname: Arumugam
authors.affiliation: Department of Clinical Pharmacology, Niigata University of Pharmacy and Applied Life Sciences, Niigata, Japan.
authors.forename: Kenichi
authors.initials: K
authors.lastname: Watanabe
authors.affiliation: Center for Translational Medicine, Temple University School of Medicine, Philadelphia, PA, USA.
authors.forename: Raj
authors.initials: R
authors.lastname: Kishore
authors.affiliation: Department of Cardiovascular Sciences, Center for Cardiovascular Regeneration, Houston Methodist Research Institute, Houston, TX, USA.|Cell and Developmental Biology, Department of Cardiothoracic Surgery, Weill Cornell Medical College of Cornell University, New York, NY, USA.
authors.forename: Prasanna
authors.initials: P
authors.lastname: Krishnamurthy
mesh_terms: D000818:Animals; D049109:Cell Proliferation / Q000235:genetics; D048909:Diabetes Complications / Q000503:physiopathology*; D055785:Gene Knockdown Techniques; D006097:Granulation Tissue / Q000503:physiopathology; D018799:Intercellular Adhesion Molecule-1 / Q000032:analysis; D053583:Interleukin-1beta / Q000378:metabolism; D008297:Male; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D018919:Neovascularization, Physiologic / Q000235:genetics; D018384:Oxidative Stress / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D062326:Re-Epithelialization / Q000235:genetics*; D015398:Signal Transduction / Q000235:genetics; D037761:Sirtuins / Q000172:deficiency* / Q000235:genetics* / Q000378:metabolism; D012867:Skin / Q000737:chemistry / Q000378:metabolism*; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D019010:Vascular Cell Adhesion Molecule-1 / Q000032:analysis
chemical_list: D053583:Interleukin-1beta; D016328:NF-kappa B; D034741:RNA, Small Interfering; D014409:Tumor Necrosis Factor-alpha; D019010:Vascular Cell Adhesion Molecule-1; D018799:Intercellular Adhesion Molecule-1; C501860:Sirt6 protein, mouse; D037761:Sirtuins
keywords: angiogenesis; diabetes; inflammation; sirtuin 6; wound healing