Siasos Gerasimos, Tousoulis Dimitris, Siasou Zoi, Stefanadis Christodoulos, Papavassiliou Athanasios G
Cardiology Unit, Hippokration Hospital, University of Athens Medical School, Greece.
Curr Med Chem. 2007;14(14):1567-72. doi: 10.2174/092986707780831087.
Shear stress represents the frictional force that the flow of blood exerts at the endothelial surface of the vessel wall and plays a central role in cell function and structure via managing several processes and contributes to the progress of atherosclerosis. It is a fact that interaction of blood flow and the endothelial surface is the critical interface for shear stress-dependent mechanotransduction. Vascular endothelial cells are equipped with numerous receptors in order to "sense" and react to mechanical forces elicited by shear stress. The intracellular signal transduction pathways and specifically the activation of protein kinases, is the second important molecular event underpinning cellular reactions to extracellular stimuli. MAPKs, comprising ERK1/2, JNKs/stress-activated protein kinases (SAPKs), and p38s, are serine/threonine protein kinases with a prominent role in cell differentiation, growth, and apoptosis, by modulating the activity of downstream target proteins and various transcription factors, hence gene expression programs. Shear stress (nonlaminar or disturbed blood flow) plays an important role in atherosclerosis, where flow conditions are characterized by low or oscillatory shear stress. Atherosclerosis is promoted by decreased shear stress, as it is associated with a suppression of functions taking place on the vascular wall, such as eNOs production and endothelial cell repair. In the presence of systemic risk factors, there is an increased tendency for atherosclerotic plaque formation, which, once formed, further disrupt flow and forward growth of the fibroinflammatory lipid plaque. Targeted inhibition of many kinase types and subtypes is an immense research field as this may lead to novel therapeutic approaches to prevent atherogenesis.
剪切应力代表血液流动在血管壁内皮表面施加的摩擦力，通过管理多个过程在细胞功能和结构中发挥核心作用，并促进动脉粥样硬化的进展。事实上，血流与内皮表面的相互作用是剪切应力依赖性机械转导的关键界面。血管内皮细胞配备有众多受体，以便“感知”由剪切应力引发的机械力并做出反应。细胞内信号转导途径，特别是蛋白激酶的激活，是支撑细胞对细胞外刺激反应的第二个重要分子事件。丝裂原活化蛋白激酶（MAPK）包括细胞外信号调节激酶1/2（ERK1/2）、c-Jun氨基末端激酶/应激激活蛋白激酶（JNK/SAPK）和p38，是丝氨酸/苏氨酸蛋白激酶，通过调节下游靶蛋白和各种转录因子的活性，从而调控基因表达程序，在细胞分化、生长和凋亡中发挥重要作用。剪切应力（非层流或紊乱血流）在动脉粥样硬化中起重要作用，在这种情况下，血流条件的特征是低剪切应力或振荡剪切应力。剪切应力降低会促进动脉粥样硬化，因为它与血管壁上发生的功能抑制有关，如内皮型一氧化氮合酶（eNOs）的产生和内皮细胞修复。在存在全身危险因素的情况下，动脉粥样硬化斑块形成的倾向增加，一旦形成，会进一步破坏血流并促进纤维炎症性脂质斑块的向前生长。对许多激酶类型和亚型的靶向抑制是一个庞大的研究领域，因为这可能会带来预防动脉粥样硬化发生的新治疗方法。
