Melatonin promotes diabetic wound healing by mediating mitochondrial function in endothelial cells through the AMPK/SIRT1/HIF-1α pathway

Objective: Diabetic wounds are open lesions that can develop on any part of the body of diabetic patients. Importantly, melatonin (Mel) exerts promotional effects on wound healing. Accordingly, this study explored the mechanism of Mel in diabetic wound healing by mediating mitochondrial function in endothelial cells. Methods: Human umbilical vein vascular endothelial cells (HUVECs) were exposed to high glucose (HG) to mimic a diabetic environment in vitro, followed by Mel treatment. Cell viability, invasion and angiogenic capacity were evaluated with CCK-8, Transwell, and tube formation assays, respectively. CD31 protein expression was determined with Western blot. Wound healing ability was evaluated in vitro, and the levels of adenosine triphosphate (ATP), reactive oxygen species (ROS), mitochondrial membrane potential (MMP), and apoptosis-related proteins (Bcl-2/Bax/CytC) were also detected. To verify the role of the AMPK/SIRT1/HIF-1 alpha pathway in diabetic wound healing, HG-induced HUVECs treated with Mel were subjected to treatment with sh-HIF-1 alpha, AMPK inhibitor (compound c), or SIRT1 inhibitor (Nicotinamide). Results: HG impaired the proliferation, invasion, angiogenesis, and wound healing ability of HUVEC, increased ROS, Bax, and CytC levels, and decreased MMP and the levels of ATP and Bcl-2. Mel facilitated viability, angiogenesis, and wound healing ability while ameliorating mitochondrial dysfunction in HG-treated HUVECs. Mel activated the AMPK/SIRT1 pathway to upregulate HIF-1 alpha in HG-treated HUVECs. HIF-1 alpha knockdown, CC, or Nicotinamide negated the effect of Mel on HG-treated HUVECs. Conclusions: Mel fosters angiogenesis and represses mitochondrial dysfunction in endothelial cells by activating the AMPK/SIRT1/HIF-1 alpha pathway, thereby promoting diabetic wound healing.