Mechanisms of Hawthorn Action in Heart Failure

山楂治疗心力衰竭的作用机制

• 批准号: 6764541
• 负责人: Barry E Bleske
• 金额: $ 17.91万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-15 至 2006-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6764541
• 关键词: alternative medicine; angiosperms; biomarker; calcium transporting ATPase; cardiovascular agents; chemoprevention; disease /disorder model; fibrosis; heart failure; heart function; laboratory mouse; medicinal plants; muscle proteins; myosins; pathologic process; pharmacokinetics; plant extracts; ventricular hypertrophy

DESCRIPTION (provided by applicant): Recent clinical studies suggest that hawthorn may be beneficial in the treatment of systolic heart failure. Basic studies, which have focused on acute effects of hawthorn on contractility and cardioprotection, have also suggested important benefits. These findings have brought hawthorn to the forefront of complementary alternative medicines for the treatment of heart failure. Clearly these limited findings need to be expanded if hawthorn or the constituents of hawthorn are to be embraced for the treatment of heart failure. One area where these findings need to be expanded is the mechanism(s) by which hawthorn may affect heart failure at a cellular level. This is the overall goal of this proposal; to determine how hawthorn, at a cellular and functional level, affects the development of systolic heart failure over time. It is hypothesized based in part on the number of compounds contained in a preparation of hawthorn that known protein and gene expression that are important in the development and maintenance of heart failure will be attenuated. To evaluate this concept this proposal is divided into three specific aims. The first specific aim (SA1) will determine the effect of hawthorn on myocardial function and corresponding contractile proteins including alpha- and beta-myosin heavy chains, sacroplasmic reticulum Ca-ATPase, and the genes that may regulate these proteins. The second specific aim (SA2) will evaluate the effect of hawthorn on the development of fibrosis. The third specific aim (SA3) will evaluate the effect of hawthorn on apoptosis. Overall these specific aims will determine the effect of hawthorn on myocardial function and known biochemical markers that are responsible for heart failure. In order to establish the mechanisms (SA1, SA2, SA3) by which hawthorn may be beneficial in heart failure an aortic constriction model in rats will be employed. This model is a practical model to work with since the development of heart failure is predictable and the hypertrophy response includes numerous phenotypic and genotypic features that are consistent with pathological cardiac hypertrophy and will address our specific aims. For this proposal hawthorn at three different dose levels will be administered at the time of surgically induced aortic constriction. Animals will be sacrificed at 5 weeks and at the time at which 50% of the placebo group develops symptomatic heart failure to address each specific aim. This study will determine how hawthorn, at a cellular and functional level, affects the development and maintenance of systolic heart failure. Completion of this study will clearly establish whether or not hawthorn has important mechanistical effects on the pathophysiology of heart failure and if so will make further studies of hawthorn in the treatment of heart failure a high priority. The results from this study will have important translation to both the basic and clinical research settings.

描述（由申请人提供）：最近的临床研究表明山楂可能有益于治疗收缩性心力衰竭。基础研究主要关注山楂对收缩力和心脏保护的急性影响，也表明了山楂的重要益处。这些发现使山楂成为治疗心力衰竭的补充替代药物的前沿。显然，如果要采用山楂或山楂成分来治疗心力衰竭，则需要扩大这些有限的发现。这些发现需要扩展的一个领域是山楂可能在细胞水平上影响心力衰竭的机制。这是本提案的总体目标；确定山楂如何在细胞和功能水平上影响收缩性心力衰竭随时间的发展。 部分基于山楂制剂中所含化合物的数量，推测对心力衰竭的发展和维持重要的已知蛋白质和基因表达将减弱。为了评估这一概念，该提案分为三个具体目标。第一个具体目标 (SA1) 将确定山楂对心肌功能和相应收缩蛋白（包括 α 和 β 肌球蛋白重链、肌浆网 Ca-ATP 酶以及可能调节这些蛋白的基因）的影响。第二个具体目标（SA2）将评估山楂对纤维化发展的影响。第三个具体目标（SA3）将评估山楂对细胞凋亡的影响。总的来说，这些具体目标将确定山楂对心肌功能和导致心力衰竭的已知生化标志物的影响。 为了建立山楂对心力衰竭有益的机制（SA1、SA2、SA3），将采用大鼠主动脉缩窄模型。该模型是一个实用的模型，因为心力衰竭的发展是可预测的，并且肥厚反应包括许多与病理性心脏肥大一致的表型和基因型特征，并将解决我们的特定目标。对于该建议，将在手术引起主动脉缩窄时施用三种不同剂量水平的山楂。动物将在 5 周时处死，此时安慰剂组 50% 的动物出现症状性心力衰竭，以实现每个特定目标。 这项研究将确定山楂如何在细胞和功能水平上影响收缩性心力衰竭的发展和维持。这项研究的完成将明确山楂是否对心力衰竭的病理生理学具有重要的机制作用，如果是这样，将使山楂治疗心力衰竭的进一步研究成为当务之急。这项研究的结果将对基础和临床研究环境产生重要的转化。