An Hyun-Jin, Lee Woo-Ram, Kim Kyung-Hyun, Kim Jung-Yeon, Kim Woon-Hae, Park Kwan-Kyu, Youn Sung Won
Department of Pathology, College of Medicine, Catholic University of Daegu Daegu, South Korea.
Department of Radiology, College of Medicine, Catholic University of Daegu Daegu, South Korea.
Int J Clin Exp Pathol. 2015 Apr 1;8(4):3971-8. eCollection 2015.
Atherosclerosis is a complex disease which involves both genetic and environmental factors in its development and progression. Shear stress is the drag force per unit area acting on the endothelium as a result of blood flow, and it plays a critical role in plaque location and progression. TGF-β1 is often regarded to have pro-atherosclerotic effect on vascular disease. TGF-β1 downstream targets Smad, for regulating a set of genes associated with atherosclerosis. Therefore, modulation of TGF-β1 and Smad expression may be the important targets for the prevention and treatment of shear stress-induced vascular disease. However, the precise mechanism of the anti-atherosclerotic effects of novel therapeutic approach has not been elucidated by using animal models regarding the shear stress-induced vascular disease. Therefore, we designed to test whether Smad decoy ODN would prevent the development of atherosclerosis in the shear stress-induced ApoE-/-mice on a western diet. We examined the effect of cast placement on the development of atherosclerosis, and the carotid artery was harvested at the sacrifice to observe histological changes. Also, we evaluated the impact of Smad decoy ODN in the regulation of genes expression related to atherosclerosis, including TGF-β1, PAI-1, and α-SMA. Our results showed that western diet with cast placement developed atherosclerosis in ApoE-/-mouse. Also, administration of Smad decoy ODN decreases the expression of TGF-β1, PAI-1, and α-SMA. These results demonstrate the potential of Smad decoy ODN to prevent the progression of atherosclerosis in ApoE-/-mouse model with western diet and shear stress.
动脉粥样硬化是一种复杂的疾病，其发生和发展涉及遗传和环境因素。剪切应力是由于血流作用于内皮细胞的单位面积拖曳力，它在斑块定位和进展中起关键作用。转化生长因子-β1（TGF-β1）通常被认为对血管疾病具有促动脉粥样硬化作用。TGF-β1的下游靶点是Smad，用于调节一组与动脉粥样硬化相关的基因。因此，调节TGF-β1和Smad的表达可能是预防和治疗剪切应力诱导的血管疾病的重要靶点。然而，关于剪切应力诱导的血管疾病，尚未通过动物模型阐明新型治疗方法抗动脉粥样硬化作用的确切机制。因此，我们设计实验来测试Smad诱饵寡核苷酸（ODN）是否能预防西方饮食喂养的、剪切应力诱导的载脂蛋白E基因敲除（ApoE-/-）小鼠发生动脉粥样硬化。我们研究了套管放置对动脉粥样硬化发展的影响，并在处死时采集颈动脉以观察组织学变化。此外，我们评估了Smad诱饵ODN对与动脉粥样硬化相关基因表达的调节作用，包括TGF-β1、纤溶酶原激活物抑制剂-1（PAI-1）和α-平滑肌肌动蛋白（α-SMA）。我们的结果表明，西方饮食加套管放置可使ApoE-/-小鼠发生动脉粥样硬化。此外，给予Smad诱饵ODN可降低TGF-β1、PAI-1和α-SMA的表达。这些结果证明了Smad诱饵ODN在预防西方饮食和剪切应力作用下的ApoE-/-小鼠模型中动脉粥样硬化进展方面的潜力。
