Shear stress sustains atheroprotective endothelial KLF2 expression more potently than statins through mRNA stabilization.
Shear stress sustains atheroprotective endothelial KLF2 expression more potently than statins through mRNA stabilization.
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DOI：
10.1016/j.cardiores.2006.07.008
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发表时间：
2006-11
影响因子：
10.8
通讯作者：
Johannes V. van Thienen;J. Fledderus;R. Dekker;J. Rohlena;Gerben A van Ijzendoorn;N. Kootstra;H. Pannekoek;A. Horrevoets
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文献类型：
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作者：
Johannes V. van Thienen;J. Fledderus;R. Dekker;J. Rohlena;Gerben A van Ijzendoorn;N. Kootstra;H. Pannekoek;A. Horrevoets
目的：转录因子KLF2被认为是内皮抗炎和抗血栓特性的重要介质。KLF2在血管树的低剪切力、动脉粥样硬化易发部位不存在，但在体外被HMG-CoA还原酶抑制剂（他汀类药物）诱导。我们研究了 KLF2 依赖性诱导内皮动脉粥样硬化保护状态的重要决定因素，以确定是否进行药物干预，例如药物干预。方法：通过定量测量 KLF2 及其下游靶基因血栓调节蛋白 (TM) 和内皮一氧化氮合酶 (eNOS) mRNA 的稳态水平和稳定性，确定人脐静脉内皮细胞中的剪切应力和他汀类药物与 TNF-α 联合作用。结果：我们证明 长时间的剪切应力具有优于他汀类药物的潜力，可以诱导 eNOS 和 TM 的 KLF2 依赖性表达，特别是在促炎细胞因子肿瘤坏死因子-α (TNF-α) 存在的情况下。这些效应可归因于剪切作用下 KLF2mRNA 的持续稳定，导致 KLF2 蛋白表达增加，并伴随 KLF2 下游靶标的强烈诱导。 KLF2mRNA 的稳定性被证明依赖于涉及磷酸肌醇 3 激酶 (PI3K) 的信号传导。结论：KLF2 稳态水平的稳定（由长期剪切应力而非他汀类药物诱导）可能对于维持炎症条件下血管内皮的静止、动脉粥样硬化保护状态至关重要。
Objective:The transcription factorKLF2is considered an important mediator of the anti-inflammatory and anti-thrombotic properties of the endothelium.KLF2is absent from low-shear, atherosclerosis-prone sites of the vascular tree but is induced by HMG-CoA reductase inhibitors (statins) in vitro. We studiedKLF2-dependent induction of important determinants of the atheroprotective status of the endothelium to determine whether pharmacological intervention, e.g. by statins, can potentially replace shear stress.Methods:Shear stress and statin effects in combination with TNF-α were determined in human umbilical vein endothelial cells by quantitative measurements of the steady-state levels and stability of mRNA forKLF2and its downstream target genes thrombomodulin (TM) and endothelial nitric oxide synthase (eNOS).Results:We demonstrate that prolonged shear stress has a potential that is superior to that of statins to induce theKLF2-dependent expression of eNOS and TM, especially in the presence of the pro-inflammatory cytokine tumor necrosis factor-α (TNF-α). These effects can be attributed to the sustained stabilization ofKLF2mRNA by shear, leading to an increasedKLF2protein expression and concomitant strong induction ofKLF2downstream targets. The stabilization ofKLF2mRNA is demonstrated to be dependent on signaling involving phosphoinositide 3-kinase (PI3K).Conclusion:The stabilization ofKLF2steady-state levels, as induced by prolonged shear stress but not by statins, may be essential for sustaining the quiescent, atheroprotective status of the vascular endothelium under inflammatory conditions.