Abstract 3596: Ablation of Nrf2 Resulted in Acceleration of Ischemia-Induced Angiogenesis
NFE2-related factor 2 (Nrf2) [nuclear factor erythroid 2-like 2 (Nfe2l2)] is an important transcription factor in the protection against oxidative stress through antioxidant response element-mediated transcriptional activation of several antioxidant enzymes. We have now investigated potential roles of Nrf2 on angiogenesis in a murine surgical model of ischemia. Ischemia was produced by femoral artery ligature in the Nrf2-deficient (Nrf2−/−) and wild type (WT) mice (n = 8 for each group). Laser Doppler perfusion analyses showed significant improvement in the ischemic/nonischemic blood flow ratio of Nrf2−/− mice compared with WT mice (0.84 ± 0.03 vs. 0.76 ± 0.02, p < 0.05) at 4 weeks after ligature. At 3 days after the ligature, the inducible expression of Nrf2 target genes, such as heme oxygenase 1 gene (HMOX1) and peroxiredoxin 1 gene (PRDX1), determined by quantitative RT-PCR analysis was markedly reduced in the ischemic hindlimbs of Nrf2−/− mice compared with those of WT mice (7.31 ± 0.76 vs. 10.03 ± 1.07 for HMOX1, p < 0.05; 0.98 ± 0.08 vs. 1.24 ± 0.07 for PRDX1, p < 0.05). The protein levels of vascular endothelial growth factor and angiopoietin 1 were significantly (p < 0.05) greater in the ischemic hindlimbs of Nrf2−/− mice than in those of WT mice. To probe for the presence of oxidative stress, we examined the extent of lipid peroxidation in the adductor muscles. The malondialdehyde levels were significantly increased in the ischemic hindlimbs of Nrf2−/− mice compared with those of WT mice. Moreover, the activities of chemokine, CC motif, ligand 2 (MCP1) and tumor necrosis factor-alpha were significantly greater in the ischemic hindlimbs of Nrf2−/− mice than in those of WT mice. Ablation of Nrf2 resulted in acceleration of ischemia-induced angiogenesis through down-regulation of antioxidant defense and an increase in inflammation.