Inhibition of CK2a accelerates skin wound healing by promoting endothelial cell proliferation through the Hedgehog signaling pathway

Diabetes is a chronic disease characterized by perturbed glucose and lipid metabolism, resulting in high blood glucose levels. Many complications induced by endothelial dysfunction can cause disability and even death of diabetic patients. Here, we found that the protein level of casein kinase 2a (CK2a) was increased in the endothelium of mice with type I diabetes (T1D) induced by streptozotocin (STZ) injection. Although a potential correlation between the protein level of CK2a and endothelial dysfunction in diabetes was established, the contribution of CK2a to the progression of endothelial dysfunction in diabetes remained largely unknown. By using CX4945 (a selective CK2a antagonist) and Si-csnk2a1 (small interfering RNA targeting CK2a), we found that inhibition of CK2a accelerated skin wound healing in T1D mice by promoting proliferation of endothelial cells. Administration of CX4945 or Si-csnk2a1 rescued the impaired Hedgehog signaling pathway in high glucose-treated human umbilical vein endothelial cells (HUVECs). Exploration of the underlying molecular mechanism revealed that the protective effect of CK2a inhibition on angiogenesis, which contributes to skin wound healing in diabetic mice, was blocked by administration of GANT61 (an inhibitor targeting the Hedgehog signaling pathway). Our findings establish CK2a as a regulator of endothelial dysfunction in diabetes and demonstrate that inhibition of CK2a accelerates skin wound healing in T1D mice by promoting endothelial cell proliferation via the Hedgehog signaling pathway.