REVERSAL OF MYOCARDIAL HYPERTROPHY IN HYPERTENSION

本项目的总体目标是研究 心肌肥厚发生和消退的机制 在高血压中。 我们的实验室已经证明， 心血管肥大的发展/消退不依赖于 机械负荷单独，但在许多方面的相互作用：心脏 压力负荷、心脏肾上腺素能系统和各种体液因素。 在过去的资助期间，我们已经表明，有几个因素可以 在肥大消退期间调节肌球蛋白同种型。 影响因素有膳食钠、儿茶酚胺等 用作抗高血压药物的药理学药剂。 我们还 表明肌球蛋白异构体的转移与血液无关， 血压、心肌质量和交感神经活动。 这些观察结果 产生了新的问题，我们设计了这个更新提案， 研究组织间质基质的结构重塑， 高血压中肥大的进行性发展。 过量胶原蛋白 众所周知，积聚会增加心脏的硬度， 它的功能和导致失败。 我们的初步数据显示， 胶原蛋白具有多种表型形式， 心肌肥厚是心脏僵硬度的一个重要指标， 除了胶原蛋白的数量之外，还包括特定胶原蛋白类型的丰度。 至于肥大的消退是有益还是有害，两个关键 肥厚后退化的概念从未建立： 胶原蛋白改变的功能后果，以及 新缩小的小心脏来应对突然的压力过载。 我们的研究结果还表明，每种抗高血压药物 对心脏的生化组成的独特影响，例如， 我们的数据显示， 根据存在的胶原蛋白或肌球蛋白的类型。 未来5年 我们将关注心脏的胶原蛋白生产， 肥大的消退是有益的还是有害的。 我们建议 检查的假设，功能和结构重塑的 心肌肥厚和心力衰竭时的间质基质， 回归后心脏的再重塑与 在胶原蛋白的产生中，胶原蛋白在影响心脏的 功能 我们将研究胶原蛋白及其表型在细胞和 分子水平，评估胶原蛋白的功能后果。 我们 具体目的是a）量化胶原蛋白及其表型， mRNA水平的变化，并测量每种基因的转录率。 表型; B）确定药物干预对 上述参数; c）阐明胶原蛋白改变的机制 在培养的心肌成纤维细胞和肌细胞中产生; d） 评估降压治疗是否使肥大消退 （α-甲基多巴、卡托普利、阿替洛尔）是有益的还是有害的。 这些 研究将概述胶原蛋白代谢的异常， 心肌肥大的发展/消退，并阐明其 对心脏功能的影响 在确定精神错乱时，我们将 确定适当的治疗是否能纠正这些变化， 直接改变心肌胶原蛋白的形成， 肥大心脏的功能受损

The overall objective of this project is to study the underlying mechanisms in the development and regression of myocardial hypertrophy in hypertension. Our laboratory has shown that the development/regression of cardiovascular hypertrophy does not depend on mechanical load alone but on the interplay of many aspects: cardiac pressure load, the cardioadrenergic system, and various humoral factors. In the past funding period we have shown that several factors can modulate myosin isoform during the regression of hypertrophy. Influential factors are dietary sodium, catecholamines, and many pharmacological agents used as antihypertensive drugs. We have also shown that the shifting of myosin isoforms is independent of blood pressure, myocardial mass and sympathetic activity. These observations generated new questions, and we have designed this renewal proposal to study the structural remodeling of the interstitial matrix during the progressive development of hypertrophy in hypertension. Excess collagen accumulations are known to increase the heart's rigidity, compromising its function and leading to failure. Our preliminary data showed that collagen has various phenotypic forms and that in the development of hypertrophy an important indicator of heart stiffness is the relative abundance of a specific collagen type, in addition to collagen quantity. As to whether regression of hypertrophy is beneficial or harmful, two key concepts in post hypertrophic regression have never been established: the functional consequences of collagen alteration, and the capacity of the newly reduced small heart to handle sudden pressure overload. Results from our study also suggest that each antihypertensive drug has a unique effect on the biochemical composition of the heart, e.g., collagen, and our data showed that functional consequences will vary according to the type of collagen or myosin present. In the next 5 years we will focus on the heart's collagen production, determining whether regression of hypertrophy is beneficial or harmful. We propose to examine the hypothesis that functional and structural remodelling of the heart's interstitial matrix in hypertrophy and heart failure and the heart's re-remodelling after regression are associated with alterations in collagen production, which plays a role in influencing cardiac function. We will study collagen and its phenotypes at cellular and molecular levels, evaluating collagen's functional consequences. Our specific aims are a) to quantify collagen and its phenotypes, identifying changes in the mRNA level and measuring the transcription rate of each phenotype; b) to determine the effect of pharmacologic intervention on the above parameters; c) to elucidate the mechanism for altered collagen production in cultured myocardial fibroblasts and myocytes; d) to evaluate whether regression of hypertrophy by antihypertensive therapy (alpha-methyldopa, captopril, atenolol) is beneficial or harmful. These studies will outline the abnormalities of collagen metabolism in the development/regression of myocardial hypertrophy and elucidate their effect on cardiac function. On identifying the derangement, we will determine if appropriate treatment corrects the changes and if such directed alteration in myocardial collagen formation improves the compromised function of the hypertrophied heart.