The Unraveling Truth About IRE1 and MicroRNAs in Diabetes

摘要

Wound healing is a well-regulated complex process that occurs as a cellular response to injury and consists of four phases: hemostasis, inflammation, proliferation, and remodeling. Many factors, such as diabetes and obesity, interfere with these stages and lead to wound healing defect. Diabetes affects approximately 170 million people worldwide, including 20.8 million in the U.S., and by 2030 these numbers are projected to double. Impaired wound healing is a major clinical problem in patients with diabetes and is the leading cause of lower-extremity amputation and comorbidity associated with diabetes. Diabetic skin ulcers are estimated to occur in 15% of all patients with diabetes and 84% of all diabetes-related lower-leg amputations. Despite current treatments, one in four patients with diabetic ulcers will have a foot amputation. Therefore, new treatment strategies for healing diabetic skin ulcers are highly needed. Impaired or delayed wound healing in diabetes is characterized by impaired angiogenesis and vas-culogenesis. Adult bone marrow progenitor cells, bone marrow-derived endothelial progenitor cells (BMPCs), can home to injured tissue and participate in the tissue repair regeneration process. However, in diabetes, BMPCs are dysfunctional (defective recruitment and reduced survival and proliferation). The mechanism of bone marrow cell dysfunction in diabetes is not yet fully understood. Endoplas-mic reticulum (ER), a multifunctional organelle involved in lipid synthesis, calcium homeostasis, protein folding, and maturation, responds to stress (diabetes, oxidative stress, and disturbance in calcium homeostasis) by inhibiting protein translation and activating protein chaperones via a process called unfolded protein response (UPR). The UPR activates signaling pathways through three major ER resident proteins: the protein kinase RNA-like ER kinase (PERK), the inositol-requiring enzyme 1 (IRE1), and the activating transcription factor (ATF6). IRE1 through its endonude-ase activity cleaves the mRNA encoding the transcription factor X-box binding protein 1 (XBP1) to splice XBP1 (sXBP1) responsible for the upregulation of various genes involved in the UPR signaling to limit protein misfolding in the ER . In addition to XBP1 splicing, IRE1α also cleaves other mRNAs of the ER membrane and microRNAs (miRNAs) , leading to their degradation through regulated IRE1α-dependent decay (RIDD) . We and others have shown that ER stress plays a major role in angiogenesis impairment and wound healing delay in diabetes.