【作者】 张伟；

【导师】 张永健；

【作者基本信息】 河北医科大学 ， 药理学， 2006， 博士

【摘要】 心肌肥厚是心脏对多种疾病包括高血压、机械负荷、心肌梗塞、心律失常、内分泌机能紊乱以及心肌收缩蛋白的基因突变的适应性反应,是心脏输出作功增加的最初代偿性机制反应。持续性的心肌肥大能够引起扩张性心肌病,心衰甚至猝死。心肌肥厚是心血管疾病病死率和发病率的独立危险因素。许多研究表明,细胞内钙离子浓度可以作为引起心肌肥厚的一种信号,是心肌肥大发生发展和相关基因表达的中心环节。血管紧张素Ⅱ(angiotensinⅡ, AngⅡ) ,肾上腺素(adrenaline, AD)和内皮素-1(endothelin-1,ET-1)等均可以通过升高细胞内钙浓度诱导心肌肥厚。血管紧张素Ⅱ(AngⅡ)具有心肌生长因子样作用,AngⅡ与AT1受体结合,通过Gq蛋白偶联受体激活包括磷脂酶C(phospholipase C, PLC)等多种磷酸脂酶,活化的磷脂酶C可加速水解细胞膜上的二磷酸肌醇磷脂(PIP2)生成两个重要的第二信使:三磷酸肌醇(inositol triphosphate, IP3)和甘油二酯(diacylglycerol, DAG),这些均能够激活蛋白激酶C(protien kinase C, PKC),使细胞内Ca2+浓度升高,已知AngⅡ不仅可以通过L-型钙通道,而且还能够引起钙库的释放增加细胞内钙离子浓度。AngⅡ介导的心肌肥大可能与其增加细胞内Ca2+有关。双苯氟嗪(dipfluzine, Dip)系由河北医科大学药学院合成的氟桂利嗪类的钙拮抗剂。经研究发现Dip通过阻断L型钙通道,从而具有抑制迟后除极和触发活动以及抗心律失常等作用。除此之外,Dip还能够改善压力超负荷引起的左室肥厚的左心室收缩和舒张功能并能够降低左室重量指数和心肌纤微直径。本实验通过细胞免疫化学、流式细胞术、激光共聚焦、分子生物学(Westen-blotting, RT-PCR)等技术研究双苯氟嗪对乳鼠培养的心肌成纤维细胞及心肌细胞心肌肥厚及其作用机制:(1)Dip对AngⅡ诱导的心肌成纤维细胞增殖、胶原合成、细胞周期以及PCNA蛋白表达的影响;(2) Dip抑制心肌成纤维增殖和胶原合成的可能机制;(3) Dip对AngⅡ诱导更多还原

【Abstract】 Cardiac hypertrophy is an adaptive response of the heart to virtually all forms of cardiac diseases, including those arising from hypertension, mechanical load, myocardial infarction, cardiac arrhythmias, endocrine disorders, and genetic mutations in cardic contractile protein genes. While the hypertrophic response is initially a compensatory mechanism that augments cardiac output, hypertrophy can lead to dilated cardiomyopathy, heart failure, and sudden death. Cardiac hypertrophy was an absolute and dangerous factor that affected mortality and morbidity of cardiovascular diseases.Numerous studies have implicated intracellular [Ca2+]i as a signal for cardiac hypertrophy. It is indicated that Ca2+ signals play a central role in the development of cardiac hypertrophic growth and gene expression.The humoral factors, including angiotensinⅡ(AngⅡ),adrenaline (AD) and endothelin-1(ET-1), induce the hypertrophic response in cardiomyocytes, also share the ability to elevate intracellular Ca2+ concentrations. Increasing evidences suggest that AngⅡmay act as a growth factor for the heart through Gq protein-coupled receptors. AngⅡactivates multiple phospholipases, including phospholipase C ( PLC ) , through binding AT1 receptor in cardiac myocytes. Activation of PLC leads to production of inositol trisphosphate (IP3) and diacylglycerol (DAG) through hydrolysis of phosphatidylinositol 4, 5-disphosphate (PIP2). These second messengers are known to cause release of Ca2+ from intracellular stores and activation of protein kinase C (PKC). It is known that AngⅡnot only increases Ca2+ influx through the L-type Ca2+ channel but also induces Ca2+ release from intracellular Ca2+ stores. Ca2+ may be an important factor in AngⅡ-mediated growth.Nowadays, angiotensin converting enzyme inhibitor and calcium channel blockers are mainly used for curing cardiac hypertrophy. Some calcium channel blockers had satisfactory anti-hypertrophy effect. So, it would have更多还原