Abstract 1211: Gene Ablation Bach-1 Leads to Suppression of Atherosclerosis in Apolipoprotein-E (Apo-E) and Bach1 Double Knockout Mice (ApoE−/ −Bach1−/ −)
Bach1 is a novel transcriptional factor governing cytoprotective programs including heme oxygenase-1 (HO-1). Mice lacking Bach-1 gene shows increased activity of HO-1 in cardiovascular system, increased phagocytic activity of macrophage, increased expression of macrophage chemotactic factor-1, suppression of vascular smooth muscle proliferation, and suppression of neointimal formation after in vivo vascular injury. However, the overall role of Bach1 in the atherosclerosis is poorly understood. In the present study, we investigated the effect of Bach1 ablation on the development of atherosclerosis by comparing ApoE-kockout (KO) mice and ApoE/Bach1 double KO mice. The homozygous ApoE/Bach1 double KO (ApoE−/ −and Bach1−/ −) mice were generated by intercrossing ApoE-KO and Bach1-KO mice, both have been back-crossed onto C57BL/6J background for at least 12 generations. There was no difference in the birth rate, fertility, growth rate between of Apo-E/Bach1 double-KO and ApoE-KO mice. After mice were fed high cholesterol diet for 8 weeks, there was no significant difference in body weight, blood pressure, and serum levels of total cholesterol between the double-KO and ApoE-KO mice. The Western blot analysis revealed that the HO-1 protein expression in the aorta, was markedly increased in double-KO mice than in ApoE-KO mice. The atherosclerotic plaque formation in the thoracic and abdominal aorta, visualized by oil-red-O staining, was reduced by 38% in Apo-E/Bach1 KO mice compared with Apo-E KO mice (P<0.01). These results suggest that atherosclerosis was inhibited in ApoE/Bach1 double KO. Bach1 appears to negatively control the activity of anti-atherosclerotic defense mechanism including HO-1 system, limiting the maximum survival level against stress. Inhibition of Bach1, conversely, may be a novel therapeutic strategy to treat atherosclerotic diseases.