Abstract
Wound healing is delayed in diabetic patients. Increased apoptosis and endothelial progenitor cell (EPC) dysfunction are implicated in delayed diabetic wound healing. Melatonin, a major secretory product of the pineal gland, promotes diabetic wound healing; however, its mechanism of action remains unclear. Here, EPCs were isolated from the bone marrow of mice. Treatment of EPCs with melatonin alleviated advanced glycation end product (AGE)-induced apoptosis and cellular dysfunction. We further examined autophagy flux after melatonin treatment and found increased light chain 3 (LC3) and p62 protein levels in AGE-treated EPCs. However, lysosome-associated membrane protein 2 expression was decreased, indicating that autophagy flux was impaired in EPCs treated with AGEs. We then evaluated autophagy flux after melatonin treatment and found that melatonin increased the LC3 levels, but attenuated the accumulation of p62, suggesting a stimulatory effect of melatonin on autophagy flux. Blockage of autophagy flux by chloroquine partially abolished the protective effects of melatonin, indicating that autophagy flux is involved in the protective effects of melatonin. Furthermore, we found that the AMPK/mTOR signaling pathway is involved in autophagy flux stimulation by melatonin. An in vivo study also illustrated that melatonin treatment ameliorated impaired wound healing in a streptozotocin-induced diabetic wound healing model. Thus, our study shows that melatonin protects EPCs against apoptosis and dysfunction via autophagy flux stimulation and ameliorates impaired wound healing in vivo, providing insight into its mechanism of action in diabetic wound healing.
Highlights
Diabetes, often referred to as diabetes mellitus, is a group of metabolic diseases in which blood glucose levels are elevated either because insulin production is inadequate or because the body’s cells do not respond properly to insulin, or both[1]
advanced glycation end product (AGE) is one of the main mechanisms responsible for vascular damage in patients with diabetes, playing an Numerous studies have shown that moderating autophagy has protective effects against various pathologies[29,30]
Li et al.[33] demonstrated that AGEs dramatically increased the expression of LC3II/I and p62 in HUVECs
Summary
Often referred to as diabetes mellitus, is a group of metabolic diseases in which blood glucose levels are elevated either because insulin production is inadequate or because the body’s cells do not respond properly to insulin, or both[1]. In 2014, it was estimated that over 422 million people throughout the world had diabetes[2], and the number is predicted to increase. Most tissue impairment caused by diabetes is not due to the loss of glucose control but to complications of diabetes, including cardiovascular disease, nerve damage (neuropathy), kidney damage (nephropathy), eye damage (retinopathy), hearing impairment, and Alzheimer’s disease. Delayed wound healing is one of the most common diabetic complications[3]. The healing of surgical wounds[4], dental extraction sockets[5], and foot ulcers[6] is retarded in diabetic patients. The pathogenesis of delayed wound healing caused by diabetes has not been fully elucidated; effective treatments are still lacking
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