Novel insights into the angiogenic function of JMJD2B in diabetic hind limb ischemia: involvement of activating Wnt/β-catenin pathway

Critical limb ischemia (CLI) is a major health problem, in which diabetes is a risk factor. Lysine Demethylase 4B (JMJD2B) is a histone demethylase. Diabetic CLI model was established in mice by streptozotocin injection and femoral artery ligation. Reduced expression of JMJD2B in lower limb muscles was observed in CLI mice with or without diabetes, accompanied by impaired blood perfusion and mobility. Adenovirus-mediated JMJD2B overexpression improved blood perfusion and angiogenesis as indicated by the alternation in CD31, α-SMA, and VEGFA expression in the lower limb of diabetic mice with CLI. In vitro, JMJD2B expression and the proliferation and tube formation ability were inhibited by high glucose and ischemic conditions in HMEC-1 cells. Overexpressed-JMJD2B contributed to angiogenesis by promoting cell proliferation, migration, and tube formation of HMEC-1 cells, as well as increasing VEGFA and SDF-1 expression. Mechanism study indicated that JMJD2B overexpression activated the Wnt/β-catenin pathway by promoting β-catenin nuclear translocation and the expression. This might lead to stimulated angiogenesis, as demonstrated by the Wnt/β-catenin inhibitor XAV-939. Overall, our study revealed that JMJD2B was down-regulated in CLI mice with diabetes and JMJD2B overexpression promoted angiogenesis probably via the activation of Wnt/β-catenin pathway.