Suhara Toshimitsu, Magrané Jordi, Rosen Kenneth, Christensen Rial, Kim Hyo-Soo, Zheng Bing, McPhie Donna L, Walsh Kenneth, Querfurth Henry
Divisions of Neurology and Cardiovascular Research, St Elizabeth's Medical Center, Tufts University, Boston, MA 02135, USA.
Neurobiol Aging. 2003 May-Jun;24(3):437-51. doi: 10.1016/s0197-4580(02)00135-5.
The application of beta-amyloid (Abeta) is cytotoxic to endothelial cells, promotes vasoconstriction and impairs nitric oxide (NO) generation or action. However, there is no information on the effect of intracellular Abeta on endothelial cell biology, although recent studies indicate that neuronal Abeta drives Alzheimer's disease pathogenesis. Since the serine-threonine kinase Akt is crucial to both neuronal and endothelial cell survival as well as eNOS activation, we investigated the effects of Abeta expression on Akt-signaling in cultured endothelial cells. Virally-encoded Abeta42 was proapoptotic and inhibitory to Akt phosphorylation in human umbilical vein endothelial cells (HUVECs). Toxicity was characterized by mitochondrial dysfunction, DNA condensation and activation of caspase-3. Substrates downstream of Akt action, GSK-3beta and eNOS, are underphosphorylated in the presence of Abeta. Constitutive activation of Akt reversed Abeta-induced toxicity and stimulated caspase-3 activity, suggesting that inhibition of Akt signaling is functionally significant. These Abeta effects were mediated, in part, through the derepression of GSK-3beta activation and correlated with reductions in NO production. We conclude that intracellular production of Abeta42 is cytotoxic to endothelial cells and that disruption of the Akt/GSK-3beta cell signaling pathway is involved.
β-淀粉样蛋白（Aβ）的应用对内皮细胞具有细胞毒性，可促进血管收缩并损害一氧化氮（NO）的生成或作用。然而，尽管最近的研究表明神经元Aβ驱动阿尔茨海默病的发病机制，但关于细胞内Aβ对内皮细胞生物学影响的信息却尚无报道。由于丝氨酸-苏氨酸激酶Akt对神经元和内皮细胞的存活以及内皮型一氧化氮合酶（eNOS）的激活都至关重要，我们研究了Aβ表达对培养的内皮细胞中Akt信号传导的影响。病毒编码的Aβ42在人脐静脉内皮细胞（HUVECs）中具有促凋亡作用，并抑制Akt磷酸化。毒性表现为线粒体功能障碍、DNA凝聚和半胱天冬酶-3的激活。在Aβ存在的情况下，Akt作用下游的底物糖原合成酶激酶-3β（GSK-3β）和eNOS的磷酸化不足。Akt的组成型激活可逆转Aβ诱导的毒性并刺激半胱天冬酶-3的活性，这表明抑制Akt信号传导在功能上具有重要意义。这些Aβ效应部分是通过解除对GSK-3β激活的抑制介导的，并且与NO生成的减少相关。我们得出结论，细胞内Aβ42的产生对内皮细胞具有细胞毒性，并且涉及Akt/GSK-3β细胞信号通路的破坏。
