REVERSAL OF MYOCARDIAL HYPERTROPHY IN HYPERTENSION

逆转高血压心肌肥厚

• 批准号: 2216189
• 负责人: Subha Sen
• 金额: $ 18.61万
• 依托单位: CLEVELAND CLINIC FOUNDATION
• 依托单位国家: 美国
• 财政年份: 1983
• 资助国家: 美国
• 起止时间: 1983-02-01 至 1997-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2216189
• 关键词: adrenergic receptor; antihypertensive agents; atenolol; captopril; cardiovascular pharmacology; catecholamines; cellular pathology; collagen; heart failure; heart function; hypertension; laboratory rat; messenger RNA; myosins; phenotype; remission /regression; ventricular hypertrophy

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.

该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 在高血压中。 我们的实验室表明 心血管肥大的发展/消退并不取决于 单独的机械负荷但取决于许多方面的相互作用：心脏 压力负荷、心肾上腺素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、儿茶酚胺等 用作抗高血压药物的药物。 我们还有 研究表明肌球蛋白亚型的转变与血液无关 压力、心肌质量和交感神经活动。 这些观察 产生了新的问题，我们设计了这个更新提案 研究间隙矩阵的结构重塑 高血压逐渐发展为肥厚。 胶原蛋白过多 众所周知，积累会增加心脏的硬度，损害 其功能并导致故障。 我们的初步数据表明 胶原蛋白具有多种表型形式，并且在发育过程中 心脏肥厚的一个重要指标是心脏僵硬度的相对值 除了胶原蛋白的数量之外，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，有两个关键 肥厚后回归的概念从未建立： 胶原蛋白改变的功能后果以及 新缩小的小心脏可以应对突然的压力过载。 我们的研究结果还表明，每种抗高血压药物都有 对心脏的生化成分有独特的影响，例如， 胶原蛋白，我们的数据表明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。 未来5年 我们将重点关注心脏的胶原蛋白生成，确定是否 肥大的消退是有益的还是有害的。 我们建议 检验以下假设：功能和结构重塑 肥厚和心力衰竭中的心脏间质基质以及 退行后心脏的重新重塑与改变相关 胶原蛋白的产生，对影响心脏功能起着重要作用 功能。 我们将研究胶原蛋白及其在细胞和 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 mRNA水平的变化并测量每个的转录率 表型； b) 确定药物干预的效果 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 评估抗高血压治疗是否可以消退肥厚 （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。 在识别出精神错乱后，我们将 确定适当的治疗是否可以纠正这些变化，以及是否可以纠正这些变化 直接改变心肌胶原形成可改善 肥大的心脏功能受损。