Department of Thoracic Surgery and Clinical Institute of Medical and Chemical Laboratory Diagnostics, University of Vienna, Austria.
Arterioscler Thromb Vasc Biol. 2010 Aug;30(8):1634-41. doi: 10.1161/ATVBAHA.110.207316. Epub 2010 May 27.
Heme oxygenase-1 (HO-1) is an antioxidative, antiinflammatory, and cytoprotective enzyme that is induced in response to cellular stress. The HO-1 promoter contains a (GT)n microsatellite DNA, and the number of GT repeats can influence the occurrence of cardiovascular diseases. We elucidated the effect of this polymorphism on endothelial cells isolated from newborns of different genotypes.
On the basis of HO-1 expression, we classified the HO-1 promoter alleles into 3 groups: short (S) (most active, GT < or = 23), medium (moderately active, GT=24 to 28), and long (least active, GT > or = 29). The presence of the S allele led to higher basal HO-1 expression and stronger induction in response to cobalt protoporphyrin, prostaglandin-J(2), hydrogen peroxide, and lipopolysaccharide. Cells carrying the S allele survived better under oxidative stress, a fact associated with the lower concentration of oxidized glutathione and more favorable oxidative status, as determined by measurement of the ratio of glutathione to oxidized glutathione. Moreover, they proliferated more efficiently in response to vascular endothelial growth factor A, although the vascular endothelial growth factor-induced migration and sprouting of capillaries were not influenced. Finally, the presence of the S allele was associated with lower production of some proinflammatory mediators, such as interleukin-1beta, interleukin-6, and soluble intercellular adhesion molecule-1.
The (GT)n promoter polymorphism significantly modulates a cytoprotective, proangiogenic, and antiinflammatory function of HO-1 in human endothelium.
血红素加氧酶-1（HO-1）是一种抗氧化、抗炎和细胞保护酶，可响应细胞应激而诱导。HO-1 启动子包含一个（GT）n 微卫星 DNA，GT 重复次数可影响心血管疾病的发生。我们阐明了该多态性对来自不同基因型新生儿的内皮细胞的影响。
根据 HO-1 表达，我们将 HO-1 启动子等位基因分为 3 组：短（S）（最活跃，GT≤23）、中（GT=24 至 28）和长（GT≥29）。S 等位基因的存在导致基础 HO-1 表达更高，并且对钴原卟啉、前列腺素 J（2）、过氧化氢和脂多糖的诱导更强。携带 S 等位基因的细胞在氧化应激下生存能力更强，这与氧化型谷胱甘肽浓度较低和更有利的氧化状态有关，这是通过测量谷胱甘肽与氧化型谷胱甘肽的比值来确定的。此外，它们对血管内皮生长因子 A 的增殖反应更有效，尽管血管内皮生长因子诱导的毛细血管迁移和发芽不受影响。最后，S 等位基因的存在与某些促炎介质（如白细胞介素-1β、白细胞介素-6 和可溶性细胞间黏附分子-1）的产生减少有关。
（GT）n 启动子多态性显著调节了人类内皮细胞中 HO-1 的一种细胞保护、促血管生成和抗炎功能。
