FOXO1参与高血压条件下异常张应变诱导的血管平滑肌细胞增殖  

The role of FOXO1 in cyclic stretch induced-proliferation of vascular smooth muscle cells during hypertension

作　　者：顾翔[1] 姜隽[1,2] 吴垒磊 杨煜晨 张萍[1] 韩海潮[1,3] 姜宗来[1] 齐颖新[1] 

机构地区：[1]上海交通大学生命科学技术学院力学生物学研究所,上海200240 [2]四川省泸州医学院附属医院血管外科,泸州646000 [3]Department of Mechanical Engineering,the University of Texas,San Antonio,USA

出　　处：《医用生物力学》2014年第5期440-446,共7页Journal of Medical Biomechanics

基　　金：国家自然科学基金资助项目(31170892;11229202;11232010);上海市青年科技启明星计划(11QA1403200)

摘　　要：目的探讨高血压条件下异常升高的周期性张应变刺激对血管平滑肌细胞(vascular smooth muscle cells,VSMCs)增殖的影响,以及Forkhead转录因子1(FOXO1)在其中可能的作用。方法构建腹主动脉缩窄高血压大鼠模型,并以假手术组为对照,应用FX-4000T体外周期性张应变加载系统,分别对VSMCs施加5%的生理性张应变和15%的高血压病理性张应变。Western blot检测VSMCs的FOXO1及p-FOXO1表达水平,Brd U法检测VSMCs增殖活性。RNA干扰技术抑制VSMCs的FOXO1表达,检测FOXO1、p-FOXO1表达以及VSMCs增殖活性变化。结果腹主动脉缩窄术后2和4周,大鼠血压较假手术大鼠明显增高。与假手术大鼠相比,高血压大鼠血管壁细胞增殖活性明显增高,同时FOXO1及p-FOXO1表达水平也显著性升高。细胞实验表明,与5%张应变组相比,15%张应变加载显著上调VSMCs的FOXO1、p-FOXO1表达水平,以及VSMCs增殖活性。静态条件下RNA干扰抑制VSMCs的FOXO1及p-FOXO1表达,VSMCs的增殖活性明显降低。结论高血压病理条件下,异常增高的周期性张应变可能通过促进FOXO1表达和磷酸化诱导VSMCs增殖。以动物模型观察现象,在细胞分子水平探讨机制,旨在明确FOXO1在高血压血管重建中的作用及其力学生物学机制,为阐明高血压血管重建的发病机理和药物治疗靶标的研究提供新的实验依据。Objective To investigate the role of pathologically increased-cyclic stretch in proliferation of vascular smooth muscle cells （VSMCs） during hypertension,and the effect of Forkhead box protein O1 （FOXO1） during this process.Methods Coarctation of abdominal aorta above kidney artery of rat was used as hypertensive animal model,and sham-operated animal as control.FX-4000 cyclic stretch loading system was used to apply 5％ physiologically cyclic stretch and 15％ pathologically cyclic stretch during hypertension on VSMCs in vitro.Western blot was used to reveal the expressions of FOXO1 and phospho-FOXO1 in VSMCs,and BrdU kit to detect the proliferation of VSMCs in vitro.By using RNA interference in static,the role of FOXO1 on cell proliferation was further detected.Results After abdominal aorta coarctation for 2 and 4 weeks,respectively,the blood pressure was significantly increased compared with the sham-operated rats.The proliferation of vascular cells in aorta of hypertensive rat was significantly increased,and so did the expressions of FOXO1 and phospho-FOXO1.In vitro experiment revealed that 15％ cyclic stretch remarkably increased the proliferation and expressions of FOXO1 and phospho-FOXO1 in VSMCs.Target siRNA transfection in static decreased the expression of FOXO1 and phospho-FOXO1,as well as the proliferation of VSMCs.Conclusions Pathologically increased-cyclic stretch may increase the expression and phosphorylation of FOXO1,subsequently modulate VSMC proliferation during hypertension.Based on animal models,this study intends to reveal the role of FOXO1 in vascular reconstruction of hypertension and the involved biomechanical mechanism,so as to make the mechanobiological mechanism of hypertension explicit and discover new target in the prevention and treatment of vascular remodeling.

关 键 词：高血压 周期性张应变 血管平滑肌细胞 Forkhead转录因子 细胞增殖 

分 类 号：R318.01[医药卫生—生物医学工程]