Expression of heme oxygenase-1 in human vascular cells is regulated by peroxisome proliferator-activated receptors
Expression of heme oxygenase-1 in human vascular cells is regulated by peroxisome proliferator-activated receptors
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DOI：
10.1161/atvbaha.107.142638
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发表时间：
2007-06-01
影响因子：
8.7
通讯作者：
Leitinger, Norbert
中科院分区：
文献类型：
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作者：
Kroenke, Gerhard;Kadl, Alexandra;Leitinger, Norbert
目的：降脂贝特类药物和胰岛素增敏噻唑烷二酮类药物激活过氧化物酶体增殖物激活受体（PPARs）可抑制血管炎症、动脉粥样硬化和再狭窄。在这里，我们研究血管保护和抗炎酶血红素氧化酶-1 （HO-1）是否受血管细胞中PPAR配体的调节。方法与结果：我们发现用PPAR配体处理人血管内皮细胞和平滑肌细胞可导致HO-1的表达。对人HO-1启动子的瞬时转染实验、突变分析和凝胶转移分析表明，PPAR α和PPAR γ通过2个PPAR响应元件对HO-1进行直接转录调控。我们证明了HO-1启动子内的临床相关多态性严重影响PPAR两种亚型的转录激活。此外，HO-1酶活性的抑制逆转了PPAR配体介导的血管平滑肌细胞增殖和环氧化酶-2表达的抑制。结论：PPAR α和PPAR γ可通过转录调控HO-1的表达，提示PPAR配体通过上调HO-1发挥抗炎和抗增殖作用。HO-1作为PPAR靶基因的发现为心血管疾病的治疗提供了新的策略，并为PPAR配体用于治疗其他慢性炎症性疾病提供了理论依据。
Objective-Activation of peroxisome proliferator-activated receptors (PPARs) by lipid-lowering fibrates and insulin-sensitizing thiazolidinediones inhibits vascular inflammation, atherosclerosis, and restenosis. Here we investigate if the vasculoprotective and anti-inflammatory enzyme heme oxygenase-1 (HO-1) is regulated by PPAR ligands in vascular cells.Methods and Results-We show that treatment of human vascular endothelial and smooth muscle cells with PPAR ligands leads to expression of HO-1. Analysis of the human HO-1 promoter in transient transfection experiments together with mutational analysis and gel shift assays revealed a direct transcriptional regulation of HO-1 by PPAR alpha and PPAR gamma via 2 PPAR responsive elements. We demonstrate that a clinically relevant polymorphism within the HO-1 promoter critically influences its transcriptional activation by both PPAR isoforms. Moreover, inhibition of HO-1 enzymatic activity reversed PPAR ligand-mediated inhibition of cell proliferation and expression of cyclooxygenase-2 in vascular smooth muscle cells.Conclusion-We demonstrate that HO-1 expression is transcriptionally regulated by PPAR alpha and PPAR gamma, indicating a mechanism of anti-inflammatory and antiproliferative action of PPAR ligands via upregulation of HO-1. Identification of HO-1 as a target gene for PPARs provides new strategies for therapy of cardiovascular diseases and a rationale for the use of PPAR ligands in the treatment of other chronic inflammatory diseases.