Yet Shaw-Fang, Layne Matthew D, Liu Xiaoli, Chen Yen-Hsu, Ith Bonna, Sibinga Nicholas E S, Perrella Mark A
Pulmonary and Critical Care Division, Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA.
FASEB J. 2003 Sep;17(12):1759-61. doi: 10.1096/fj.03-0187fje. Epub 2003 Jul 3.
To examine the role of heme oxygenase (HO)-1 in the pathophysiology of vascular diseases, we generated mice deficient in both HO-1 and apolipoprotein E (HO-1-/-apoE-/-). Despite similar total plasma cholesterol levels in response to hypercholesterolemia, HO-1-/-apoE-/- mice, in comparison with HO-1+/+apoE-/- mice, had an accelerated and more advanced atherosclerotic lesion formation. In addition to greater lipid accumulation, these advanced lesions from HO-1-/-apoE-/- mice contained macrophages and smooth muscle alpha-actin-positive cells. We further tested the role of HO-1 on neointimal formation in a mouse model of vein graft stenosis. Autologous vein grafts in HO-1-/- mice showed robust neointima consisting of alpha-actin-positive vascular smooth muscle cells (VSMC) 10 days after surgery in comparison to the smaller neointima formed in autologous vein grafts in HO-1+/+ mice. However, at 14 days after surgery, the neointima from composite vessels of HO-1-/- mice was composed mainly of acellular material, indicative of substantial VSMC death. VSMC isolated from HO-1-/- mice were susceptible to oxidant stress, leading to cell death. Our data demonstrate that HO-1 plays an essential protective role in the pathophysiology of atherosclerosis and vein graft stenosis.
为了研究血红素加氧酶（HO）-1在血管疾病病理生理学中的作用，我们培育了HO-1和载脂蛋白E双缺陷小鼠（HO-1-/-apoE-/-）。尽管在高胆固醇血症情况下总血浆胆固醇水平相似，但与HO-1+/+apoE-/-小鼠相比，HO-1-/-apoE-/-小鼠的动脉粥样硬化病变形成加速且更严重。除了更多的脂质蓄积外，这些来自HO-1-/-apoE-/-小鼠的严重病变还含有巨噬细胞和平滑肌α-肌动蛋白阳性细胞。我们进一步在静脉移植物狭窄小鼠模型中测试了HO-1对内膜形成的作用。与HO-1+/+小鼠自体静脉移植物中形成的较小内膜相比，HO-1-/-小鼠的自体静脉移植物在术后10天显示出由α-肌动蛋白阳性血管平滑肌细胞（VSMC）组成的强大内膜。然而，术后14天，HO-1-/-小鼠复合血管的内膜主要由无细胞物质组成，表明大量VSMC死亡。从HO-1-/-小鼠分离的VSMC对氧化应激敏感，导致细胞死亡。我们的数据表明，HO-1在动脉粥样硬化和静脉移植物狭窄的病理生理学中起重要的保护作用。
