基于应力相位角理论的冠状动脉粥样硬化机制探讨

The initial changes of atherosclerosis(AS) is the increased permeability of endothelial cells of arteries, which affects the structure and functions of smooth muscle leading to endothelial transformation and finally the formation of AS. The primary reason for the differential incidence of AS is the hemodynamical difference of different arteries. The forces acting on the endothelium include wall shear stress and circumferential stress. Both of them have action on the endothelial cells simultaneously and regulate the their phenotypes. The angle between WSS and CS was a newly described hemodynamical feature named as stress phase angle, briefed as SPA. The SPA is negative 180 degree in coronary arteries where AS is most serious, whereas it is zero degree in aorta where AS is less dangerous. The hemodynamic simulator was developed to test the SPA hypothesis in bovine aorta endothelial cells. The result indicated that the gene expression profile is atherosclerotic phenotype when the WSS and CS are out-of-phase(SPA is negative 180 degree),compared with that at 0 degree of SPA which is athero-protective phenotype. The similar gene expression profiling was demonstrated in coronary endothelial cells from rabbit in vivo. We also tested the gene expression profile in human coronary and aorta endothelial cells. Currently no more studies was reported on the role of CS or the united action of CS and WSS in the pathogenesis of AS. The present program will investigate the united role of CS and WSS(SPA) in the atherosclerotic gene expression profile in coronary endothelial cells，screen the AS-related genes of coronary artery and explore the possibility to reverse the atherosclerotic gene expression phenotype by congjugtaed linoleic acid(CLA).

血流动力学差异是不同部位动脉粥样硬化(AS)发生率不同的主因。作用于内皮细胞的力有流体对管壁的剪应力（WSS）和环形张力（CS）。前期发现二者同时作用于内皮细胞，调节其表型。二者间的相位差为应力相位角（SPA）, 系血流动力学新特点。在AS最易发生的冠状动脉处二者不同相,SPA为负180度, 而主动脉处二者同相，SPA为0度。用研制的血流动力学模拟仪模拟SPA为负180度时，BAEC基因表达谱为AS性表型（ASG）; 在家兔和人冠状动脉内皮细胞（CEC）也获相似结果。SPA为0度时，为动脉保护性基因表达谱（APG）, 与主动脉内皮细胞（AEC）基因表达谱类似。 CEC的ASG多于APG，平衡易被打破，易发生AS，而AEC则相反。研究首次探讨AS时CS或CS 和WSS的相互作用，将验证CEC的SPA特点使之出现ASG, 从50种已知基因中确认CEC的AS标志物，探讨用药物CLA逆转ASG。

背景：.血流动力学差异是不同部位动脉粥样硬化(AS)发生率不同的主因。作用于内皮细胞的力有流体对管壁的剪应力（WSS）和环形张力（CS）。前期发现二者同时作用于内皮细胞，调节其表型。二者间的相位差为应力相位角（SPA）, 系血流动力学新特点。在AS最易发生的冠状动脉处二者不同相,SPA为负180度, 而主动脉处二者同相，SPA为0度。..内容：.⑴. 动脉粥样硬化易感基因和冠状动脉内皮细胞特异性标志物的筛选。⑵.了解不同步SPA-180°在动脉粥样硬化发病机理中的作用。⑶．抗动脉粥样硬化物质CLA对内皮细胞基因表达谱的影响。..结果：.用自行研制的血流动力学模拟仪模拟SPA为负180度时，BAEC基因表达谱为AS性表型（ASG）; 在家兔和人冠状动脉内皮细胞（CEC）也获相似结果。SPA为0度时，为动脉保护性基因表达谱（APG）, 与主动脉内皮细胞（AEC）基因表达谱类似。 CEC的ASG多于APG，平衡易被打破，易发生AS，而AEC则相反。.一、在体外，能够利用血流动力学模拟仪模拟体内冠状动脉的血流动力学新特点-—SPA为-180°。 将SPA为-180°的作用力作用于培养中的牛主动脉内皮细胞（BAEC），检测50种已知的与动脉粥样硬化有关的基因与SPA为-180°的关系，是否表现为动脉粥样硬化基因表达谱：首先表现为， SPA为-180°时内皮细胞的基因表达为：ET1升高，而COX2与 NO下降。以这三种基本基因的变化作为监测指标，探讨了其他47种基因的基本变化规律。.二、在体内，家兔的SPA与体外结果一致：冠状动脉处的SPA为-180°， 而主动脉等处的SPA为0°。冠状动脉处的血管内皮细胞的基因表达与上述体外实验结果基本类似。体内外实验结果均验证了SPA理论。..意义：.首次探讨了AS时CS或CS 和WSS可相互作用，证明了CEC的SPA特点是ASG, 从50种已知基因中确认了CEC的AS标志物，探讨药物耦合亚麻酸CLA能够逆转ASG。⑴．初步确立了动脉粥样硬化发生新理论体系SPA。⑵．初步筛选出动脉血管内皮细胞的标志物。⑶．初步表明药物CLA能够改变血管内皮细胞基因表达谱（50种基因）。 ⑷．建立了心血管疾病研究的新工具与新模型。