Molecular mechanism of endothelial growth arrest by laminar shear stress
Molecular mechanism of endothelial growth arrest by laminar shear stress
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DOI：
10.1073/pnas.170282597
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发表时间：
2000-08-15
影响因子：
11.1
通讯作者：
Chien, S
中科院分区：
文献类型：
--
作者：
Lin, K;Hsu, PP;Chien, S
本研究旨在阐明层流切应力抑制内皮细胞生长的机制。牛主动脉内皮细胞在3达因（1达因= 10 μ N）/cm（2）或更高的层流剪切应力作用24小时后，肿瘤抑制基因p53增加，但在1.5达因/cm（2）时没有增加。剪切诱导p53增加的机制之一是其在c-Jun N末端激酶磷酸化后的稳定化。为了研究剪切诱导的p53反应的后果，我们发现，长时间的层流剪切应力导致生长停滞蛋白GADD 45（生长停滞和DNA损伤诱导蛋白45）和p21（cip 1）的增加，以及视网膜母细胞瘤基因产物磷酸化的减少。我们的研究结果表明，长时间的层流剪切应力引起持续的p53激活，诱导GADD 45和p21（cip 1）的上调。细胞周期蛋白依赖性激酶的抑制和视网膜母细胞瘤蛋白的低磷酸化导致内皮细胞周期停滞。这种通过层流剪切应力抑制内皮细胞增殖的作用可以通过防止动脉树的直线部分中的动脉粥样硬化形成来发挥重要的稳态功能，所述动脉树的直线部分不断地经受高水平的层流剪切。
This study was designed to elucidate the mechanism underlying the inhibition of endothelial cell growth by laminar shear stress. Tumor suppressor gene p53 was increased in bovine aortic endothelial cells subjected to 24 h of laminar shear stress at 3 dynes (1 dyne = 10 mu N)/cm(2) or higher, but not at 1.5 dynes/cm(2). One of the mechanisms of the shear-induced increase in p53 is its stabilization after phosphorylation by c-Jun N-terminal kinase. To investigate the consequence of the shear-induced p53 response, we found that prolonged laminar shear stress caused increases of the growth arrest proteins GADD45 (growth arrest and DNA damage inducible protein 45) and p21(cip1), as well as a decrease in phosphorylation of the retinoblastoma gene product. Our results suggest that prolonged laminar shear stress causes a sustained p53 activation, which induces the up-regulation of GADD45 and p21(cip1). The resulting inhibition of cyclin-dependent kinase and hypophosphorylation of retinoblastoma protein lead to endothelial cell cycle arrest. This inhibition of endothelial cell proliferation by laminar shear stress may serve an important homeostatic function by preventing atherogenesis in the straight part of the arterial tree that is constantly subjected to high levers of laminar shearing.