Temporal gradient in shear but not steady shear stress induces PDGF-A and MCP-1 expression in endothelial cells -: Role of NO, NFκB, and egr-1
Temporal gradient in shear but not steady shear stress induces PDGF-A and MCP-1 expression in endothelial cells -: Role of NO, NFκB, and egr-1
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DOI：
10.1161/01.atv.19.4.996
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发表时间：
1999-04-01
影响因子：
8.7
通讯作者：
Frangos, JA
中科院分区：
文献类型：
--
作者：
Bao, XP;Lu, CY;Frangos, JA
为了区分剪切梯度和稳定剪切对人内皮细胞血小板衍生生长因子a （PDGF-A）和单核细胞趋化蛋白-1 （MCP-1）表达的影响，研究人员创建了三个明确的层流曲线。流动剖面（最大剪应力为16达因/厘米(2)）为斜坡流（剪应力在流动开始时平稳过渡）、阶梯流（剪应力在流动开始时突然施加）和脉冲流（剪应力仅施加3 s）。斜坡流仅诱导少量PDGF-A表达，不增加MCP-I表达。与斜坡流相比，阶梯流在1.5小时时分别使PDCF-A和MCP-1 mRNA水平增加3倍和2倍。相比之下，脉冲流在1.5小时内使PDGF-A和MCP-1的表达增加了6倍和7倍，并且这种高水平持续了至少4小时。这些结果表明，突变（脉冲流和阶梯流的开始）和稳定突变（斜坡流和阶梯流的稳定成分）的时间梯度分别刺激和减少PDGF-A和MCP-1的表达。NO合成酶抑制剂ng -氨基- l -精氨酸（L-NAA）可显著增强阶梯流诱导的MCP-1和PDGF-A的表达，降低脉冲流诱导的MCP-1和PDGF-A的表达，且呈剂量依赖性。NO供体精胺- nonoate （SPR/NO）剂量依赖性地降低冲动流诱导的MCP-1和PDGF-A的表达。此外，发现脉冲流刺激持续（4小时）I κ pa b - α降解和egr-1 mRNA诱导。L-NAA抑制了I κ pa b - α的降解，而SPR/NO增加了I κ pa b - α的再合成。L-NAA和SPR/NO均能抑制egr-1在血流刺激后4小时的脉冲血流诱导能力。结果表明，稳定剪切和NO供体诱导的NO均通过下调MCP-1和PDCF-A的转录因子NF kappa B和egr-1来抑制剪切诱导的MCP-1和PDCF-A的时间梯度表达，而脉冲流诱导的NO通过上调转录因子来刺激MCP-1和PDCF-A的表达。上述结果表明，剪切和稳定剪切在体内动脉粥样硬化中具有不同的作用。
Three well-defined laminar flow profiles were created to distinguish the influence of a gradient in shear and steady shear on platelet-derived growth factor A (PDGF-A) and monocyte chemoattractant protein-1 (MCP-1) expression in human endothelial cells. The flow profiles (16 dyne/cm(2) maximum shear stress) were ramp flow (shear stress smoothly transited at flow onset), step flow (shear stress abruptly applied at flow onset), and impulse flow (shear stress abruptly applied for 3 s only). Ramp flow induced only minor expression of PDGF-A and did not increase MCP-I expression. Step flow increased PDCF-A and MCP-1 mRNA levels 3- and 2-fold at 1.5 hours, respectively, relative to ramp flow. In contrast, impulse flow increased PDGF-A and MCP-1 expression 6- and 7-fold at 1.5 hours, and these high levels were sustained for at least 4 hours. These results indicate that a temporal gradient in sheer (impulse flow and the onset of step flow) and steady sheer (ramp flow and the steady component of step flow) stimulates and diminishes the expression of PDGF-A and MCP-1, respectively. NO synthase inhibitor NG-amino-L-arginine (L-NAA) was found to markedly enhance MCP-1 and PDGF-A expression induced by step flow, but decrease their expression induced by impulse flow, in a dose-dependent manner. NO donor spermine-NONOate (SPR/NO) dose-dependently reduced the MCP-1 and PDGF-A expression induced by impulse flow. Moreover, impulse flow was found to stimulate sustained (4 hours) I kappa B-alpha degradation and egr-1 mRNA induction. L-NAA prevented I kappa B-alpha degradation, whereas SPR/NO increased I kappa B-alpha resynthesis 2 hours after impulse now. Both L-NAA and SPR/NO inhibited the impulse flow inducibility of egr-1 4 hours after the flow stimulation. The results show that both NO induced by steady shear and NO donor inhibit temporal gradient in shear-induced MCP-1 and PDCF-A expression by downregulation of their respective transcription factors NF kappa B and egr-1, whereas NO induced by impulse flow stimulates MCP-1 and PDCF-A expression by upregulation of the transcription factors. The above findings suggest distinct roles of temporal gradient in shear and steady shear in atherogenesis in vivo.