Mechanisms of Hawthorn Action in Heart Failure

描述(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。基础研究侧重于山楂对心脏收缩和保护的急性影响，也表明了重要的益处。这些发现将山楂带入了治疗心力衰竭的补充替代药物的前沿。显然，如果要将山楂或山楂的成分用于治疗心力衰竭，这些有限的发现需要扩大。这些发现需要扩大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(S)。这就是这项建议的总体目标；确定山楂在细胞和功能水平上如何随着时间的推移影响收缩性心力衰竭的发展。这部分是基于山楂制剂中包含的化合物数量的假设，即在心力衰竭的发展和维持中重要的已知蛋白质和基因表达将减弱。为了评估这一概念，本提案分为三个具体目标。第一个特定目标(SA1)将确定山楂对心肌功能和相应的收缩蛋白的影响，包括α-和β-肌球蛋白重链、骶质网Ca-ATPase以及可能调节这些蛋白的基因。第二个特定目标(SA2)将评估山楂对纤维化发展的影响。第三个特定目标(SA3)将评估山楂对细胞凋亡的影响。总体而言，这些特定的目标将决定山楂对心肌功能和已知的导致心力衰竭的生化标记物的影响。 为了建立山楂对心力衰竭有益的机制(SA1、SA2、SA3)，我们将采用大鼠主动脉收缩模型。这个模型是一个实用的模型，因为心力衰竭的发展是可预测的，肥厚反应包括许多与病理性心肌肥厚一致的表型和基因特征，并将解决我们的特定目标。根据这项建议，在外科手术引起的主动脉收缩时，将给予三种不同剂量水平的山楂。动物将在5周后被处死，当安慰剂组中50%的人出现症状性心力衰竭时，以满足每个特定的目标。 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。这项研究的完成将清楚地确定山楂是否对心力衰竭的病理生理学具有重要的机制作用，如果是这样的话，将使山楂在治疗心力衰竭方面的进一步研究成为优先事项。这项研究的结果将对基础和临床研究环境都有重要的影响。

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.