Duscher Dominik, Januszyk Michael, Maan Zeshaan N, Whittam Alexander J, Hu Michael S, Walmsley Graham G, Dong Yixiao, Khong Sacha M, Longaker Michael T, Gurtner Geoffrey C
Stanford, Calif.; Linz, Austria; and Munich, Germany.
From the Hagey Laboratory, Division of Plastic Surgery, Department of Surgery, Stanford University School of Medicine; the Section of Plastic Surgery, Department of Surgery, Johannes Kepler University; and the Department of Plastic Surgery and Hand Surgery, Technical University Munich.
Plast Reconstr Surg. 2017 Mar;139(3):695e-706e. doi: 10.1097/PRS.0000000000003072.
A hallmark of diabetes mellitus is the breakdown of almost every reparative process in the human body, leading to critical impairments of wound healing. Stabilization and activity of the transcription factor hypoxia-inducible factor (HIF)-1α is impaired in diabetes, leading to deficits in new blood vessel formation in response to injury. In this article, the authors compare the effectiveness of two promising small-molecule therapeutics, the hydroxylase inhibitor dimethyloxalylglycine and the iron chelator deferoxamine, for attenuating diabetes-associated deficits in cutaneous wound healing by enhancing HIF-1α activation.
HIF-1α stabilization, phosphorylation, and transactivation were measured in murine fibroblasts cultured under normoxic or hypoxic and low-glucose or high-glucose conditions following treatment with deferoxamine or dimethyloxalylglycine. In addition, diabetic wound healing and neovascularization were evaluated in db/db mice treated with topical solutions of either deferoxamine or dimethyloxalylglycine, and the efficacy of these molecules was also compared in aged mice.
The authors show that deferoxamine stabilizes HIF-1α expression and improves HIF-1α transactivity in hypoxic and hyperglycemic states in vitro, whereas the effects of dimethyloxalylglycine are significantly blunted under hyperglycemic hypoxic conditions. In vivo, both dimethyloxalylglycine and deferoxamine enhance wound healing and vascularity in aged mice, but only deferoxamine universally augmented wound healing and neovascularization in the setting of both advanced age and diabetes.
This first direct comparison of deferoxamine and dimethyloxalylglycine in the treatment of impaired wound healing suggests significant therapeutic potential for topical deferoxamine treatment in ischemic and diabetic disease.
糖尿病的一个标志是人体几乎所有修复过程的破坏，导致伤口愈合严重受损。糖尿病患者体内转录因子缺氧诱导因子（HIF）-1α的稳定性和活性受损，导致损伤后新血管形成不足。在本文中，作者比较了两种有前景的小分子疗法——羟化酶抑制剂二甲基草酰甘氨酸和铁螯合剂去铁胺，通过增强HIF-1α激活来减轻糖尿病相关的皮肤伤口愈合缺陷的有效性。
在用去铁胺或二甲基草酰甘氨酸处理后，在常氧或低氧以及低糖或高糖条件下培养的小鼠成纤维细胞中测量HIF-1α的稳定性、磷酸化和反式激活。此外，在用去铁胺或二甲基草酰甘氨酸局部溶液处理的db/db小鼠中评估糖尿病伤口愈合和新血管形成，并在老年小鼠中比较这些分子的疗效。
作者表明，去铁胺在体外低氧和高血糖状态下稳定HIF-1α表达并改善HIF-1α的反式活性，而在高血糖低氧条件下二甲基草酰甘氨酸的作用明显减弱。在体内，二甲基草酰甘氨酸和去铁胺均可增强老年小鼠的伤口愈合和血管生成，但只有去铁胺在老年和糖尿病情况下普遍增强伤口愈合和新血管形成。
这首次对去铁胺和二甲基草酰甘氨酸在治疗伤口愈合受损方面的直接比较表明，局部使用去铁胺治疗缺血性和糖尿病性疾病具有显著的治疗潜力。
