INITIATION OF MYOCARDIAL HYPERTROPHY IN HYPERTENSION

高血压引起心肌肥厚

• 批准号: 2223882
• 负责人: Subha Sen
• 金额: $ 21.56万
• 依托单位: CLEVELAND CLINIC FOUNDATION
• 依托单位国家: 美国
• 财政年份: 1993
• 资助国家: 美国
• 起止时间: 1993-12-01 至 1996-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2223882
• 关键词: complementary DNA; growth /development; heart function; hypertension; immunocytochemistry; in situ hybridization; muscle proteins; myocardium disorder; pathology; protein biosynthesis; protein signal sequence; radioimmunoassay; remission /regression; spontaneous hypertensive rat; ventricular hypertrophy

It is established that the mechanism for the initiation and/or regression of myocardial hypertrophy cannot be fully explained by blood pressure control alone. We have shown the evidence for the existence of factor (s) other than blood pressure control that are responsible for an increase in myocardial growth. The hypothesis we want to examine is that development of hypertrophy is initiated by a signal (mechanical or humoral) to the myocardium, which in turn produces a soluble factor that is responsible for triggering protein synthesis and myocardial cell growth. We have identified a soluble factor in the hypertrophied myocardium of spontaneously hypertensive rats (SHR) using myocytes as our bioassay system. The factor has been purified to its homogeneity and partially sequenced. It is a novel peptide with a molecular weight of 12,500 daltons. We have named this factor myotrophin. Recently, we have completed purification and partial sequencing of myotrophin from human cardiomyopathic heart. When myotrophin was added to neonatal cells in culture, the cells showed an enlargement in size that corresponds to a dose-dependent fashion. Furthermore, myotrophin caused a four-fold increased in connexin (gap junction protein) nd a two-fold increase in the total myosin transcript level, associated wit ha selective increase in beta myosin heavy chain expression. At the EM level, myotrophin causes accelerated organization and maturation of the myofibril within 48 hrs. after its addition. More importantly, we have raised specific antibodies against myotrophin and developed a bot blot assay to quantify myotrophin. Our preliminary data showed that myotrophin concentration is increased significantly in the hypertrophied ventricles of SHR and cardiomyopathic human compared to that in normals. Thus suggested that myotrophin may be an important factor in the hypertrophying process. Furthermore, we have isolated a partial cDNA clone for myotrophin and by using a specific probe (RMyo69A), the myotrophin mRNA size was found to be 6 Kb. Our goal for the next five years is to complete the sequencing of and to fully characterized myotrophin, quantity myotrophin (mRNA and protein) in the heart and other tissues during growth and evolution of hypertrophy in SHR and normal pathophysiological significance by determine its role in the initiation and development of cardiac myotrophin may play an important role in the development of hypertrophy. The proposed experiments will demonstrate that myotrophin may be controlling key for the development of cardiac hypertrophy. Continued research may yield information on the mechanism which translates cardiac load and myocardial stress into biochemical messages leading to protein synthesis. Demonstrating the role of myotrophin in initiating myocardial hypertrophy will help in the therapeutic planning for patients with hypertensive heart disease, especially in the development of an appropriate antagonist.

已确定启动和/或消退的机制 血压不能完全解释心肌肥厚的原因 独自控制。 我们已经证明了因子存在的证据 (s)除了控制血压之外， 增加心肌生长。 我们要检验的假设是， 肥大的发展是由信号（机械或 体液的）到心肌，这反过来又产生可溶性因子， 负责触发蛋白质合成和心肌细胞 增长我们已经在肥大症患者中发现了一种可溶性因子 以心肌细胞为模型， 生物测定系统 该因子已被纯化至其同质性， 部分排序。 它是一种新型肽，分子量为 12,500道尔顿。 我们把这种因子命名为肌营养因子。 最近我们 人肌营养素的完全纯化和部分测序 心肌病性心脏 当肌营养素加入新生细胞中， 在培养中，细胞显示出对应于一个细胞大小的增大。 剂量依赖性方式。 此外，肌营养因子引起四倍的 连接蛋白（间隙连接蛋白）增加， 与HA选择性增加相关的总肌球蛋白转录水平 β-肌球蛋白重链表达。 在EM水平，肌营养因子 导致体内肌原纤维的加速组织和成熟 48小时的添加后。 更重要的是，我们提出了具体的 针对肌营养因子的抗体，并开发了bot印迹分析来定量 肌营养素 我们的初步数据显示， 在SHR肥厚的心室中显著增加， 与正常人相比。 因此建议 肌营养素可能是肥大过程中的一个重要因素。 此外，我们还分离了肌营养素的部分cDNA克隆， 使用特异性探针（RMyo 69 A），发现肌营养素mRNA大小 6 KB。 我们未来五年的目标是完成测序 和充分表征的肌营养素，量肌营养素（mRNA和 蛋白质）在心脏和其他组织的生长和进化过程中， 高血压大鼠心肌肥厚及其正常病理生理意义 确定其在心脏病的发生和发展中的作用 肌营养素可能在肥大的发展中起重要作用。 所提出的实验将证明肌营养因子可能是 控制心脏肥大发展的关键。 继续 研究可能会产生关于心脏翻译机制的信息， 负荷和心肌应力转化为生化信息， 合成. 证明肌营养素在启动心肌细胞凋亡中的作用 肥大将有助于患者的治疗计划， 高血压性心脏病，特别是在发展中国家， 合适的对手。