RTA-dh404 decreased oxidative stress in mice ischemic limbs and augmented efficacy of therapeutic angiogenesis by intramuscular injection of adipose-derived regenerative cells in the limbs.

Although an intramuscular injection of angiogenic cells to ischemic limbs with peripheral artery disease is a therapeutic option to rescue patients by augmenting neovascularization in the limbs, oxidative stress in the limbs may accelerate apoptosis of the injected cells and thereby reduce the therapeutic effect. In this study involving mice with ischemic lower limbs, whether daily oral administration of RTA-dh404, which is an activator of nuclear factor erythroid 2-related factor 2 (Nrf2) with antioxidant activity, could reduce oxidative stress in the limbs and suppress apoptosis of adipose-derived regenerative cells (ADRCs) injected in the limbs, eventually augmenting neovascularization in the limbs, was evaluated. The tissue expression of Nrf2 and concentrations of total antioxidant capacity and superoxide dismutase in the mice ischemic limbs were higher in the RTA-dh404-treated mice than in the control treated mice, and oxidative stress in the limbs of the RTA-dh404 treated mice was decreased. The day after an intramuscular injection of human ADRCs into ischemic lower limbs of immunodeficient mice, the number of apoptotic ADRCs in the ischemic limbs was decreased by approximately 25% in the RTA-dh404-treated mice compared to the control mice. Fourteen days after cell injection, neovascularization and the salvage ratio were increased by approximately 10% and 63%, respectively, in the ischemic limbs in the RTA-dh404-treated mice compared to the control mice. Pretreatment of ischemic limbs by daily oral administration of RTA-dh404 may augment the effect of therapeutic angiogenesis using an intramuscular injection of ADRCs into the ischemic limbs.