Department of Biomedical Engineering, Indiana University Purdue University Indianapolis, Indianapolis, IN 46202, USA.
Life Sci. 2013 Aug 14;93(5-6):194-200. doi: 10.1016/j.lfs.2013.06.011. Epub 2013 Jun 24.
Endothelial cells are the interface between hemodynamic fluid flow and vascular tissue contact. They actively translate physical and chemical stimuli into intracellular signaling cascades which in turn regulate cell function, and endothelial dysfunction leads to inflammation and diseased conditions. For example, atherosclerosis, a chronic vascular disease, favorably develops in regions of disturbed fluid flow and low shear stress. Apoptosis, or programmed cell death, must be properly regulated to maintain homeostasis in the vascular wall. The loss of apoptosis control, as seen in low shear stress regions, is implicated in various diseases such as atherosclerosis and cancer. Death-associated protein kinase (DAPK) is a pro-apoptotic regulator for various cell types that is localized in the cell cytoskeleton and regulates changes in cytoplasm associated with apoptosis. Yet its role in endothelial cells remains unclear. Laminar shear stress inhibits cytokine, oxidative stress, and serum starvation induced endothelial apoptosis, while extended shearing elicit structural changes and cell alignment. We hypothesize that DAPK potentially plays a role in attenuating endothelial apoptosis in response to shear stress. We found that shear stress regulates DAPK expression and apoptotic activity in endothelial cells. In fact, shear stress alone induces DAPK and apoptosis, but has the opposite effect in the presence of apoptotic triggers such as tissue necrosis factor α (TNFα). This review summarizes mechanisms of endothelial mechanotransduction and apoptosis, and explores the potential of DAPK as a novel signaling pathway involved in mediating protective effects of shear stress on the vasculature.
内皮细胞是血流动力学流体流动与血管组织接触的界面。它们将物理和化学刺激主动转化为细胞内信号级联，从而调节细胞功能，内皮功能障碍导致炎症和病变。例如，动脉粥样硬化是一种慢性血管疾病，在血流紊乱和低切应力区域有利地发展。细胞凋亡或程序性细胞死亡必须得到适当的调节，以维持血管壁的内稳态。低切应力区域失去凋亡控制与各种疾病有关，如动脉粥样硬化和癌症。死亡相关蛋白激酶 (DAPK) 是一种促凋亡调节剂，可调节各种细胞类型的细胞凋亡，定位于细胞胞质骨架，调节与凋亡相关的细胞质变化。然而，其在血管内皮细胞中的作用尚不清楚。层流剪切力抑制细胞因子、氧化应激和血清饥饿诱导的内皮细胞凋亡，而延长剪切力会引起结构变化和细胞排列。我们假设 DAPK 可能在响应剪切力时在减轻内皮细胞凋亡中发挥作用。我们发现剪切力调节内皮细胞中 DAPK 的表达和凋亡活性。事实上，单独的剪切力诱导 DAPK 和凋亡，但在存在凋亡触发因子（如肿瘤坏死因子α (TNFα)）时会产生相反的效果。这篇综述总结了内皮细胞机械转导和凋亡的机制，并探讨了 DAPK 作为一种新的信号通路，参与介导剪切力对血管的保护作用的潜力。
