Mechanisms of Hawthorn Action in Heart Failure

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期心力衰竭。基础研究集中在山楂对收缩力和心脏保护的急性作用上，也提出了重要的益处。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，如果山楂或山楂的成分被用于治疗心力衰竭，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；在细胞和功能水平上确定山楂如何随时间影响收缩期心力衰竭的发展。假设部分基于山楂制剂中所含化合物的数量，已知的蛋白质和基因表达在心力衰竭的发展和维持中很重要，它们将被减弱。为了评估这一概念，本建议分为三个具体目标。第一个特异性目的（SA1）将确定山核桃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，骶浆网ca - atp酶，以及可能调节这些蛋白的基因。第二个特异性目标（SA2）将评估山楂对纤维化发展的影响。第三个特异性目的（SA3）将评估山楂对细胞凋亡的影响。总的来说，这些特定的目标将确定山楂对心肌功能和已知的导致心力衰竭的生化标志物的影响。

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.