Statin-mediated cytoprotection of human vascular endothelial cells: a role for Kruppel-like factor 2-dependent induction of heme oxygenase-1
Statin-mediated cytoprotection of human vascular endothelial cells: a role for Kruppel-like factor 2-dependent induction of heme oxygenase-1
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DOI：
10.1111/j.1538-7836.2007.02787.x
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发表时间：
2007-12-01
影响因子：
10.4
通讯作者：
Mason, J. C.
中科院分区：
文献类型：
--
作者：
Ali, F.;Hamdulay, S. S.;Mason, J. C.
背景资料：血红素氧合酶-1（HO-1）通过在血管系统中发挥抗炎、抗增殖、抗凋亡和抗氧化作用，防止动脉粥样硬化和移植后血管病变。我们注意到HO-1的作用与3-羟基-3-甲基戊二酰辅酶A（HMG-CoA）还原酶抑制剂（他汀类药物）的作用之间存在重叠。这导致研究HO-1在他汀类药物介导的原代人内皮细胞（EC）细胞保护中的作用，以及Kruppel样因子2（KLF 2）调节HO-1功能的能力。方法/结果：用阿托伐他汀处理人脐静脉和主动脉EC显著上调HO-1启动子活性、mRNA表达和蛋白表达，增加HO-1酶活性，如升高的细胞内胆红素IX α所示。这种作用是间接的，依赖于HMG-CoA还原酶和香叶基香叶基化的抑制，而不依赖于一氧化氮或mRNA稳定性的变化。阿托伐他汀可保护内皮细胞免受活性氧自由基的产生和H2 O2诱导的损伤。HO-1抑制，小干扰RNA（siRNA）或锌原卟啉IX，废除阿托伐他汀介导的细胞保护。阿托伐他汀上调KLF 2表达，而KLF 2 siRNA减弱他汀诱导的HO-1及其相关的抗氧化细胞保护作用。铁螯合、腺病毒介导的铁蛋白过表达或在培养基中添加胆绿素逆转了HO-1和KLF 2 siRNA的抑制作用，表明胆色素和铁蛋白介导了他汀类药物诱导的HO-1的抗氧化作用。结论：我们已经确定了人血管内皮细胞中KLF 2和HO-1之间的新联系，表明阿托伐他汀介导的HO-1上调及其相关的抗氧化作用是KLF 2依赖性的。KLF 2和HO-1之间的关系可能是他汀类药物血管保护作用的重要组成部分。
Background: Heme oxygenase-1 (HO-1), by exerting anti-inflammatory, antiproliferative, antiapoptotic and antioxidant effects in the vasculature, protects against atherosclerosis and post-transplant vasculopathy. We noted the overlap between the effects of HO-1 and those attributed to 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins). This led to an investigation of the role of HO-1 in statin-mediated cytoprotection in primary human endothelial cells (ECs), and the ability of Kruppel-like factor 2 (KLF2) to regulate HO-1 function. Methods/results: Treatment of human umbilical vein and aortic ECs with atorvastatin significantly upregulated HO-1 promoter activity, mRNA expression and protein expression, increasing HO-1 enzymatic activity as shown by raised intracellular bilirubin IX alpha. This effect was indirect, dependent upon inhibition of HMG-CoA reductase and geranylgeranylation, and independent of nitric oxide or changes in mRNA stability. Atorvastatin protected ECs against the generation of reactive oxygen species and H2O2-induced injury. HO-1 inhibition, with small interfering RNA (siRNA) or zinc protoporphyrin IX, abrogated atorvastatin-mediated cytoprotection. Atorvastatin upregulated KLF2 expression, whereas KLF2 siRNA attenuated statin-induced HO-1 and its associated antioxidant cytoprotective effects. Iron chelation, adenoviral-mediated overexpression of ferritin or supplementation of culture media with biliverdin reversed the inhibitory effects of HO-1 and KLF2 siRNA, suggesting that bile pigments and ferritin mediate the antioxidant actions of statin-induced HO-1. Conclusions: We have identified a novel link between KLF2 and HO-1 in human vascular ECs, demonstrating that atorvastatin-mediated HO-1 upregulation, and its associated antioxidant effect, is KLF2-dependent. The relationship between KLF2 and HO-1 is likely to represent an important component of the vasculoprotective profile of statins.