Hypertrophy, Heart Failure and PKC

肥厚、心力衰竭和 PKC

基本信息

批准号：
7214740
负责人：
DARIA MOCHLY-ROSEN
金额：
$ 37.63万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-04-01 至 2009-03-31
项目状态：
已结题

项目摘要

Protein kinase C (PKC) isozymes play a key role in insult-induced cardiac remodeling and the progression to heart failure (HF). Conflicting data on the role of individual PKC isozymes in modulating these functions have been reported, in part due to the use of PKC isozyme non-selective pharmacological tools. Our research identified PKC isozyme-selective inhibitors and activators, which we apply to determine the role of individual isozymes in normal and diseased heart. We identified peptide inhibitors and activators for each isozyme and found that the peptides can be effectively delivered into the heart, in vivo. Using these PKC regulating peptides, we previously showed opposing roles for specific PKC isozymes in various functions; we showed that ePKC activation or delta PKC inhibition provides cardioprotection from ischemia in vitro, ex vivo and recently in vivo. We also found that our isozyme-specific peptide regulators of PKC remain effective when continuously delivered in vivo, for 10 days. Therefore, for the first time, we can determine whether these PKC-regulating peptides can prevent, enhance or reduce cardiac remodeling and transition to heart failure, a study that requires regulation of PKC in a sustained fashion. Due to the limitations of animal models for cardiac remodeling and HF, we plan to use 3 different models, and use the peptides as selective pharmacological tools to determine the role of each PKC isozyme in the development of HF. The first model involves pressure overload using transverse aortic constriction in mice. The second uses pressure overload in hypertensive Dahl rats, which develop reliable cardiac remodeling and heart failure after initiation of a high salt diet. The third model follows post myocardial infarction-induced cardiac remodeling and HF in mice. Peptide regulators of individual isozymes (activators or inhibitors) will be delivered in a sustained fashion at different times during the course of the disease to determine the role of each PKC isozyme in the development of adaptive and maladaptive remodeling and the transition to heart failure. Together, these studies will identify the PKC isozyme(s) that should be targeted for the development of new therapeutics for human heart failure, especially if PKC-based pharmacotherapy is considered

蛋白激酶 C (PKC) 同工酶在损伤引起的心脏重塑和心力衰竭 (HF) 进展中发挥关键作用。关于单个 PKC 同工酶在调节这些功能中的作用，已有报道存在相互矛盾的数据，部分原因是使用 PKC 同工酶非选择性药理学工具。我们的研究确定了 PKC 同工酶选择性抑制剂和激活剂，我们将其用于确定单个同工酶在正常和患病心脏中的作用。我们鉴定了每种同工酶的肽抑制剂和激活剂，并发现这些肽可以在体内有效地递送到心脏中。使用这些 PKC 调节肽，我们之前展示了特定 PKC 同工酶在各种功能中的相反作用；我们表明，ePKC 激活或 delta PKC 抑制可在体外、离体和最近体内提供针对缺血的心脏保护作用。我们还发现，我们的 PKC 同工酶特异性肽调节剂在体内连续递送 10 天时仍然有效。因此，我们第一次可以确定这些 PKC 调节肽是否可以预防、增强或减少心脏重塑和向心力衰竭的转变，这项研究需要以持续的方式调节 PKC。由于心脏重塑和心力衰竭动物模型的局限性，我们计划使用3种不同的模型，并使用肽作为选择性药理学工具来确定每种PKC同工酶在心力衰竭发展中的作用。第一个模型涉及使用小鼠横向主动脉缩窄的压力超载。第二种方法是在高血压达尔大鼠中使用压力超负荷，这些大鼠在开始高盐饮食后会出现可靠的心脏重塑和心力衰竭。第三个模型遵循心肌梗塞后诱导的小鼠心脏重塑和心力衰竭。各个同工酶（激活剂或抑制剂）的肽调节剂将在疾病过程中的不同时间以持续的方式递送，以确定每种 PKC 同工酶在适应性和适应不良重塑的发展以及向心力衰竭的转变中的作用。总之，这些研究将确定用于开发人类心力衰竭新疗法的 PKC 同工酶，特别是考虑基于 PKC 的药物疗法时