Biomechanical forces in atherosclerosis-resistant vascular regions regulate endothelial redox balance via phosphoinositol 3-kinase/akt-dependent activation of Nrf2
Biomechanical forces in atherosclerosis-resistant vascular regions regulate endothelial redox balance via phosphoinositol 3-kinase/akt-dependent activation of Nrf2
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DOI：
10.1161/circresaha.107.152942
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发表时间：
2007-09-28
影响因子：
20.1
通讯作者：
Gimbrone, Michael A., Jr.
中科院分区：
文献类型：
--
作者：
Dai, Guohao;Vaughn, Saran;Gimbrone, Michael A., Jr.
局部模式的生物力学力量所经历的内皮细胞（EC）在不同的血管几何形状似乎发挥了重要作用，在调节EC功能，并确定区域动脉粥样硬化的易感性，即使在面对全身性的危险因素。为了研究生物力学力如何调节EC氧化还原稳态，动脉粥样硬化形成中的一个重要致病因素，我们在2种原型动脉剪切应力波形下培养了人EC，“atheroprone”和“atheroprotective”，它们来自体内2个不同的血管区域，通常对动脉粥样硬化“敏感”或“抵抗”。我们证明动脉粥样硬化保护流降低EC细胞内氧化还原水平，保护EC免受氧化应激诱导的损伤。为了确定控制这种细胞反应的分子机制，我们研究了几种主要的氧化/抗氧化途径，发现动脉粥样硬化保护流上调某些抗氧化基因，并强烈激活转录因子Nrf 2。使用小干扰RNA抑制Nrf 2表达结合全基因组转录谱分析的策略，我们确定了Nrf 2激活的下游靶点，并将Nrf 2确定为动脉粥样硬化保护性血流引起的内皮氧化还原平衡变化的关键决定因素。此外，我们发现动脉粥样硬化保护性血流通过磷酸肌醇3-激酶/Akt通路激活Nrf 2，并且这种激活在小鼠主动脉的抗动脉粥样硬化和动脉粥样硬化敏感区域中发生差异。两者合计，我们的数据表明，血流动力学力量存在于动脉粥样硬化抵抗和血管系统的敏感区域差异调节EC氧化还原状态和抗氧化电位。氧化还原稳态的这些改变主要是Nrf 2及其下游转录靶点的磷酸肌醇3-激酶/Akt依赖性激活的结果。
Local patterns of biomechanical forces experienced by endothelial cells (ECs) in different vascular geometries appear to play an essential role in regulating EC function and determining the regional susceptibility to atherosclerosis, even in the face of systemic risk factors. To study how biomechanical forces regulate EC redox homeostasis, an important pathogenic factor in atherogenesis, we have cultured human ECs under 2 prototypic arterial shear stress waveforms, "atheroprone" and "atheroprotective," which were derived from 2 distinct vascular regions in vivo that are typically "susceptible" or "resistant" to atherosclerosis. We demonstrate that atheroprotective flow decreases EC intracellular redox level and protects ECs against oxidative stress-induced injury. To identify the molecular mechanisms that control this cellular response, we examined several major oxidative/antioxidative pathways and found that atheroprotective flow upregulated certain antioxidant genes and strongly activated the transcription factor Nrf2. Using a strategy of small interfering RNA inhibition of Nrf2 expression combined with genome-wide transcriptional profiling, we determined the downstream targets of Nrf2 activation and identified Nrf2 as a critical determinant for the changes in endothelial redox balance exerted by atheroprotective flow. In addition, we showed that atheroprotective flow activates Nrf2 via the phosphoinositol 3-kinase/Akt pathway, and this activation occurs differentially in atherosclerosis-resistant and atherosclerosis-susceptible regions of the mouse aorta. Taken together, our data demonstrate that hemodynamic forces present in atherosclerosis-resistant and -susceptible regions of the vasculature differentially regulate EC redox state and antioxidant potential. These alterations in redox homeostasis are primarily the result of the phosphoinositol 3-kinase/Akt-dependent activation of Nrf2 and its downstream transcriptional targets.