INITIATION OF MYOCARDIAL HYPERTROPHY IN HYPERTENSION

已经确定了启动和/或回归的机制 血压不能完全解释心肌肥厚 一个人控制。我们已经证明了因子存在的证据。 (S)除了血压控制，其他人都负责 心肌生长增加。我们要检验的假设是 肥大的发展是由一个信号(机械或 体液)到心肌，进而产生一种可溶的因子 负责触发蛋白质合成和心肌细胞 成长。我们已经在肥厚症患者体内发现了一种可溶性因子 自发性高血压大鼠(SHR)心肌细胞的研究 生物测定系统。该因子已被提纯到其同质性，并且 部分测序。它是一种新的多肽，其分子量为 12500道尔顿。我们将这个因子命名为肌营养素。最近，我们有 人肌营养因子的纯化及部分序列测定 心肌病心脏。当肌营养素被添加到新生儿细胞中时 培养后，细胞大小增大，相当于 剂量依赖的时尚。此外，肌营养因子引起四倍的 增加了连接蛋白(缝隙连接蛋白)，增加了两倍 与选择性增加相关的总肌球蛋白转录水平 在β肌球蛋白重链中表达。在EM水平，肌营养因子 加速肌原纤维的组织和成熟 48小时。在它相加之后。更重要的是，我们已经提出了具体的 抗肌营养素抗体，并建立了BOT印迹分析来定量 肌营养素。我们的初步数据显示，肌营养素浓度 在肥厚的自发性高血压大鼠和高血压大鼠肥厚的脑室 有心肌病的人与正常人相比。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，我们还分离到了肌营养素的部分cdna克隆。 使用特定的探针(RMyo69A)，发现肌营养素mRNA的大小为 为6 KB。我们未来五年的目标是完成测序 肌营养因子、数量肌营养因子(mRNAs和 蛋白质)在心脏和其他组织的生长和进化中 自发性高血压大鼠的肥大及正常的病理生理意义 确定其在心脏疾病发生和发展中的作用 肌营养素可能在肥大的发生发展中起重要作用。 拟议的实验将证明肌营养素可能是 控制心肌肥厚发展的关键。续 研究可能会产生关于心脏翻译机制的信息 负荷和心肌应激进入导致蛋白质的生化信息 综合。肌营养素在启动心肌梗死中的作用 肥大将有助于制定治疗计划 高血压性心脏病，尤其是在高血压的发展过程中 合适的对抗者。

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.