Bach1 plays an important role in angiogenesis through regulation of oxidative stress
Farina Mohamad Yusoff, Tatsuya Maruhashi, Ki-ichiro Kawano, Ayumu Nakashima, Kazuaki Chayama, Satoshi Tashiro, Kazuhiko Igarashi, Yukihito Higashi
Abstract
Bach1 is a known transcriptional repressor of the heme oxygenase-1 (HO-1) gene. The purpose of this study was to determine whether angiogenesis is accelerated by genetic ablation of Bach1 in a mouse ischemic hindlimb model. Hindlimb ischemia was surgically induced in wild-type (WT) mice, Bach1-deficient (Bach1−/−) mice, apolipoprotein E-deficient (ApoE−/−) mice, and Bach1/ApoE double-knockout (Bach1−/−/ApoE−/−) mice. Blood flow recovery after hindlimb ischemia showed significant improvement in Bach1−/− mice compared with that in WT mice. Bach1-/-/ApoE-/- mice showed significantly improved blood flow recovery compared with that in ApoE−/− mice to the level of that in WT mice. Migration of endothelial cells in ApoE−/− mice was significantly decreased compared with that in WT mice. Migration of endothelial cells significantly increased in Bach1-/-/ApoE-/- mice compared with that in ApoE−/− mice to the level of that in WT mice. The expression levels of HO-1, peroxisome proliferator-activated receptor γ co-activator-1α, angiopoietin 1, and fibroblast growth factor 2 in endothelial cells isolated from Bach1-/-/ApoE-/- mice were significantly higher than those in ApoE−/− mice. Oxidative stress assessed by anti-acrolein antibody staining in ischemic tissues and urinary 8-isoPGF2α excretion were significantly increased in ApoE−/− mice compared with those in WT and Bach1−/− mice. Oxidative stress was reduced in Bach1-/-/ApoE-/- mice compared with that in ApoE−/− mice. These findings suggest that genetic ablation of Bach1 plays an important role in ischemia-induced angiogenesis under the condition of increased oxidative stress. Bach1 could be a potential therapeutic target to reduce oxidative stress and potentially improve angiogenesis for patients with peripheral arterial disease.