FOXO4-knockdown suppresses oxidative stress-induced apoptosis of early pro-angiogenic cells and augments their neovascularization capacities in ischemic limbs

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We assessed whether FOXO4-knockdown EPCs (FOXO4KD-EPCs) could suppress the oxidative stress-induced apoptosis and augment the neovascularization capacity in ischemic limbs.We transfected small interfering RNA (siRNA) targeted against FOXO4 to EPCs cultured from human peripheral mononuclear cells. In western blotting analyses, FOXO4 siRNA-transfected EPCs (FOXO4 KD -EPCs) showed 45% knockdown of FOXO4 and decreased expressions of pro-apoptotic proteins such as Bim and cleaved caspase-3. The FOXO4 knockdown significantly reduced the percentage of TUNEL-positive apoptotic EPCs induced by H2O2 in the flow cytometry analysis. Intramuscular injection of FOXO4 KD -EPCs to hind-limb ischemia rats significantly increased ischemic/non-ischemic hind-limb blood flow ratio and capillary density of the ischemic adductor muscle after 4 days compared to the injection of Nega-EPCs. FOXO4 KD -EPCs showed anti-apoptosis capacity, which may have contributed to neovascularization in ischemic tissues.