Dimethyl itaconate: An effective antioxidant for promoting angiogenesis under oxidative stress

Angiogenesis is an important physiological process in the human body. When ischemic diseases occur, the ischemic and hypoxic environment induces excessive production of reactive oxygen species (ROS) within cells, which inhibits angiogenesis and leads to poor prognosis. Therefore, finding antioxidants that can eliminate excessive ROS to promote angiogenesis is crucial for the treatment of ischemic diseases. In this work, we investigate the antioxidant effects of dimethyl itaconate (DMI) by using an oxidative stress model in human umbilical vein endothelial cells (HUVECs). Our results demonstrate that DMI significantly reduces excessive ROS in cells under oxidative stress. DMI could protect mechanical properties of HUVECs from oxidative stress. The Young's modulus of HUVECs was 10.0 ± 1.4 kPa after treatment with H₂O₂. However, the Young's modulus increased to 24.42 ± 1.4 kPa when HUVECs were co-incubated with H₂O₂ and DMI (40 μg mL^-1). DMI also maintained cell morphology and cytoskeletal integrity. Meanwhile, DMI alleviates mitochondrial dysfunction by enhancing mitochondrial membrane potential (MMP) and increasing adenosine triphosphate (ATP) levels. The excellent antioxidant effects of DMI result from upregulating the expression levels of superoxide dismutase 2 and catalase, significantly leading to the removal of intracellular excessive ROS. With protecting HUVECs from oxidative stress damage, DMI promotes cell migration and angiogenesis. Consequently, this work not only elaborates on the mechanism by which DMI promotes angiogenesis by anti-oxidative stress, but also provides a new therapeutic option for the treatment of ischemic diseases.