Watari Yuichiro, Yamamoto Yoshiyuki, Brydun Andrei, Ishida Takafumi, Mito Shinji, Yoshizumi Masao, Igarashi Kazuhiko, Chayama Kazuaki, Ohshima Tetsuya, Ozono Ryoji
Department of Medicine and Molecular Science, Hiroshima University Graduate School of Biomedical Sciences, Hiroshima, Japan.
Hypertens Res. 2008 Apr;31(4):783-92. doi: 10.1291/hypres.31.783.
This study was designed to determine whether Bach1 gene ablation leads to suppression of atherosclerosis in apolipoprotein E (Apo E)/Bach1 double knockout (DKO) mice. Apo E/Bach1 DKO mice were generated by intercrossing Apo E knockout (KO) and Bach1 KO mice. The animals were fed a high-fat diet for 8 weeks, and the atherosclerotic plaques in the thoracic and abdominal aorta were visualized by oil red O staining. In DKO mice, the total plaque area was reduced by 32% compared with that in Apo E KO mice. In DKO mice, heme oxygenase-1 (HO-1) was upregulated in the endothelium and, to a lesser extent, in vascular smooth muscles. In atherosclerotic plaques in Apo E KO mice and DKO mice, HO-1 was abundantly expressed in the endothelium and macrophages. Urine excretion of 8-iso-prostaglandin (PG) F2alpha, a marker for lipid peroxidation, was reduced in DKO mice compared with that in Apo E KO mice. The effects of Bach1 ablation on the plaque area and 8-iso-PG F2alpha excretion were almost completely abolished by treating DKO mice with Sn protoporphyrin, an inhibitor of HO activity. Disruption of the Bach1 gene in Apo E KO mice caused inhibition of atherosclerosis through upregulation of HO-1. Inhibition of Bach1, conversely, may be a novel therapeutic strategy to treat atherosclerotic diseases.
本研究旨在确定Bach1基因缺失是否会抑制载脂蛋白E（Apo E）/Bach1双敲除（DKO）小鼠的动脉粥样硬化。通过将Apo E敲除（KO）小鼠和Bach1 KO小鼠杂交产生Apo E/Bach1 DKO小鼠。给这些动物喂食高脂饮食8周，并用油红O染色观察胸主动脉和腹主动脉中的动脉粥样硬化斑块。在DKO小鼠中，总斑块面积比Apo E KO小鼠减少了32%。在DKO小鼠中，血红素加氧酶-1（HO-1）在内皮细胞中上调，在血管平滑肌中上调程度较小。在Apo E KO小鼠和DKO小鼠的动脉粥样硬化斑块中，HO-1在内皮细胞和巨噬细胞中大量表达。与Apo E KO小鼠相比，DKO小鼠中脂质过氧化标志物8-异前列腺素（PG）F2α的尿排泄减少。用HO活性抑制剂锡原卟啉处理DKO小鼠后，Bach1缺失对斑块面积和8-异PG F2α排泄的影响几乎完全消除。Apo E KO小鼠中Bach1基因的破坏通过上调HO-1导致动脉粥样硬化的抑制。相反，抑制Bach1可能是治疗动脉粥样硬化疾病的一种新的治疗策略。
