title: N-Acetylcysteine accelerates amputation stump healing in the setting of diabetes.
abstract: Over 60% of lower extremity amputations are performed in patients with diabetes and peripheral arterial disease, and at least 25% require subsequent reamputation due to poor surgical site healing. The mechanisms underlying poor amputation stump healing in the setting of diabetes are not understood.N-acetylcysteine (NAC) is known to promote endothelial cell function and angiogenesis and may have therapeutic benefits in the setting of diabetes. We tested the hypothesis that NAC alters the vascular milieu to improve healing of amputation stumps in diabetes using a novelin vivomurine hindlimb ischemia-amputation model. Amputation stump tissue perfusion and healing were evaluated in C57BL/6J adult mice with streptozotocin-induced diabetes. Compared with controls, mice treated with daily NAC demonstrated improved postamputation stump healing, perfusion, adductor muscle neovascularization, and decreased muscle fiber damage. Additionally, NAC stimulated HUVEC migration and proliferation in a phospholipase C β-dependent fashion and decreased Gαq palmitoylation. Similarly, NAC treatment also decreased Gαq palmitoylation in ischemic and nonischemic hindlimbsin vivoIn summary, we demonstrate that NAC accelerates healing of amputation stumps in the setting of diabetes and ischemia. The underlying mechanism appears to involve a previously unrecognized effect of NAC on Gαq palmitoylation and phospholipase C β-mediated signaling in endothelial cells.-Zayed, M. A., Wei, X., Park, K., Belaygorod, L., Naim, U., Harvey, J., Yin, L., Blumer, K., Semenkovich, C. F.N-acetylcysteine accelerates amputation stump healing in the setting of diabetes.
authors.affiliation: Section of Vascular Surgery, Department of Surgery, Washington University School of Medicine, St. Louis, Missouri, USA; zayedm@wustl.edu.|Department of Surgery, St. Louis Veterans Affairs Health Care System, St. Louis, Missouri, USA.
authors.forename: Mohamed A
authors.initials: MA
authors.lastname: Zayed
authors.affiliation: Division of Endocrinology, Metabolism, and Lipid Research, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri, USA.
authors.forename: Xiachao
authors.initials: X
authors.lastname: Wei
authors.affiliation: Section of Vascular Surgery, Department of Surgery, Washington University School of Medicine, St. Louis, Missouri, USA.
authors.forename: Kyoung-Mi
authors.initials: KM
authors.lastname: Park
authors.affiliation: Section of Vascular Surgery, Department of Surgery, Washington University School of Medicine, St. Louis, Missouri, USA.
authors.forename: Larisa
authors.initials: L
authors.lastname: Belaygorod
authors.affiliation: Section of Vascular Surgery, Department of Surgery, Washington University School of Medicine, St. Louis, Missouri, USA.
authors.forename: Uzma
authors.initials: U
authors.lastname: Naim
authors.affiliation: Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, Missouri, USA.
authors.forename: Joseph
authors.initials: J
authors.lastname: Harvey
authors.affiliation: Division of Endocrinology, Metabolism, and Lipid Research, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri, USA.
authors.forename: Li
authors.initials: L
authors.lastname: Yin
authors.affiliation: Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, Missouri, USA.
authors.forename: Kendall
authors.initials: K
authors.lastname: Blumer
authors.affiliation: Division of Endocrinology, Metabolism, and Lipid Research, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri, USA.|Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, Missouri, USA.
authors.forename: Clay F
authors.initials: CF
authors.lastname: Semenkovich
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology*; D000672:Amputation Stumps; D000818:Animals; D003921:Diabetes Mellitus, Experimental; D006614:Hindlimb / Q000098:blood supply / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D017382:Reactive Oxygen Species / Q000378:metabolism; D014945:Wound Healing / Q000187:drug effects*
chemical_list: D017382:Reactive Oxygen Species; D000111:Acetylcysteine
keywords: Gαq; NAC; arterial perfusion; peripheral arterial disease