Zayed Mohamed A, Wei Xiachao, Park Kyoung-Mi, Belaygorod Larisa, Naim Uzma, Harvey Joseph, Yin Li, Blumer Kendall, Semenkovich Clay F
Section of Vascular Surgery, Department of Surgery, Washington University School of Medicine, St. Louis, Missouri, USA;
Department of Surgery, St. Louis Veterans Affairs Health Care System, St. Louis, Missouri, USA.
FASEB J. 2017 Jun;31(6):2686-2695. doi: 10.1096/fj.201601348R. Epub 2017 Mar 9.
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. -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 novel murine 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 hindlimbs In 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. -acetylcysteine accelerates amputation stump healing in the setting of diabetes.
超过60%的下肢截肢手术是在患有糖尿病和外周动脉疾病的患者中进行的，并且由于手术部位愈合不良，至少25%的患者需要随后进行再次截肢。糖尿病患者截肢残端愈合不良的潜在机制尚不清楚。N-乙酰半胱氨酸（NAC）已知可促进内皮细胞功能和血管生成，并且在糖尿病环境中可能具有治疗益处。我们使用一种新型的小鼠后肢缺血-截肢模型，测试了NAC改变血管微环境以改善糖尿病患者截肢残端愈合的假设。在链脲佐菌素诱导的糖尿病C57BL/6J成年小鼠中评估截肢残端组织灌注和愈合情况。与对照组相比，每日接受NAC治疗的小鼠截肢后残端愈合、灌注、内收肌新生血管形成均得到改善，肌肉纤维损伤减少。此外，NAC以磷脂酶Cβ依赖性方式刺激人脐静脉内皮细胞（HUVEC）迁移和增殖，并降低Gαq棕榈酰化。同样，NAC治疗也降低了缺血和非缺血后肢的Gαq棕榈酰化。总之，我们证明NAC可加速糖尿病和缺血情况下截肢残端的愈合。潜在机制似乎涉及NAC对内皮细胞中Gαq棕榈酰化和磷脂酶Cβ介导的信号传导的一种先前未被认识的作用。——扎耶德，M.A.，魏，X.，帕克，K.，别拉伊戈罗德，L.，奈姆，U.，哈维，J.，尹，L.，布卢默，K.，塞门科维奇，C.F.——N-乙酰半胱氨酸加速糖尿病情况下截肢残端的愈合
