REVERSAL OF MYOCARDIAL HYPERTROPHY IN HYPERTENSION

这个项目的总体目标是研究潜在的 心肌肥厚发生和消退的机制 在高血压方面。我们的实验室已经证明 心血管肥厚的发展/消退不依赖于 机械负荷本身，但对许多方面的相互作用：心脏 压力负荷、心脏肾上腺素系统和各种体液因素。 在过去的资助期中，我们已经表明，有几个因素可以 在肥厚消退过程中调节肌球蛋白亚型。 影响因素有饮食中的钠、儿茶酚胺和许多 用作抗高血压药物的药理药剂。我们还有 表明肌球蛋白亚型的移动不受血液的影响 压力、心肌质量和交感神经活动。这些观察结果 产生了新的问题，我们将此续订提案设计为 研究牙周组织中间质基质的结构重塑 高血压患者肥大的进行性发展。过剩的胶原蛋白 众所周知，积聚会增加心脏的僵硬，损害 它的功能和导致的失败。我们的初步数据显示 胶原蛋白具有多种表型形式，在骨质疏松症的发育过程中 心脏硬度的一个重要指标是心脏肥大 丰富的特定胶原蛋白类型，除了胶原蛋白的数量。 关于肥厚消退是有益还是有害，有两个关键 肥厚后回归的概念从未被确立过： 胶原蛋白改变的功能后果，以及 新减少的小心脏能应对突发的压力超负荷。 我们的研究结果还表明，每种降压药都有 对心脏生化成分的独特影响，例如， 胶原蛋白，我们的数据显示，功能后果会有所不同 根据存在的胶原蛋白或肌球蛋白的类型。在未来5年内 我们将重点研究心脏胶原蛋白的产生，确定 肥大消退是有益的，也是有害的。我们建议 检验这样一种假设，即功能和结构的重塑 心脏间质基质在肥厚和心力衰竭中的作用 心脏退化后的重塑与改变有关 在胶原蛋白的产生中，这在影响心脏 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。我们的 具体目标是a)量化胶原蛋白及其表型，识别 基因转录水平的变化及转录速率的测定 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)至 评价降压治疗对肥厚消退的影响 (甲基多巴、卡托普利、阿替洛尔)是有益的或有害的。这些 研究将概述胶原代谢的异常在 心肌肥厚的发展/消退及其机制 对心脏功能的影响。在确定错乱后，我们将 确定适当的处理是否纠正了更改，如果是 心肌胶原蛋白形成的定向改变改善了 肥大的心脏功能受损。

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.