Hypertrophy, Heart Failure and PKC

肥厚、心力衰竭和 PKC

• 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
• 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
• 来源: https://reporter.nih.gov/project-details/7214740
• 关键词: Activator Appliances; Amino Acids; Animal Model; Area; Cardiac; Cells; Cessation of life; Class; Conflict (Psychology); Constriction procedure; Dahl Hypertensive Rats; Data; Development; Diet; Disease; Heart; Heart Hypertrophy; Heart failure; Human; Hypertrophy; In Vitro; Individual; Ischemia; Isoenzymes; Knockout Mice; Modeling; Molecular; Mus; Myocardial Infarction; Peptides; Pharmacotherapy; Play; Process; Protein Kinase C; Proteins; Pump; Regulation; Reporting; Research; Role; Site; Sodium Chloride; Syndrome; Therapeutic; Time; Week; base; day; genetic manipulation; in vivo; inhibitor/antagonist; novel; novel therapeutics; pressure; prevent; protein kinase C-delta; receptors for activated C kinase; response; tool

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)同工酶在创伤所致的心脏重构和心力衰竭(HF)的进展中起关键作用。关于个别PKC同工酶在调节这些功能中的作用的相互矛盾的数据已有报道，部分原因是PKC同工酶非选择性药理学工具的使用。我们的研究确定了PKC同工酶选择性抑制物和激活物，我们应用它们来确定单个同工酶在正常和疾病心脏中的作用。我们确定了每种同工酶的多肽抑制物和激活剂，并发现这些多肽可以在体内有效地输送到心脏。利用这些PKC调节肽，我们先前显示了特定的PKC同工酶在不同功能中的相反作用；我们发现ePKC激活或Delta PKC抑制在体外、体外和最近的体内都能提供心肌保护。我们还发现，我们的PKC同工酶特异性多肽调节剂在体内连续给药10天后仍然有效。因此，我们第一次可以确定这些PKC调节多肽是否可以预防、增强或减少心脏重构和向心力衰竭的过渡，这项研究需要以持续的方式调节PKC。由于心脏重构和心力衰竭动物模型的局限性，我们计划使用三种不同的模型，并使用这些多肽作为选择性的药理学工具来确定每种PKC同工酶在心力衰竭发生发展中的作用。第一种模型是利用小鼠的腹主动脉横向收缩来实现压力超负荷。第二种使用高血压Dahl大鼠的压力超负荷，在开始高盐饮食后，这些大鼠会出现可靠的心脏重塑和心力衰竭。第三种模型是心肌梗死后诱发的小鼠心脏重塑和心力衰竭。在疾病病程的不同时间，将以持续的方式递送单个同工酶的多肽调节剂(激活剂或抑制物)，以确定每种PKC同工酶在适应性和非适应性重塑和向心力衰竭的过渡中所起的作用。总之，这些研究将确定PKC同工酶(S)是开发人类心力衰竭新疗法的靶点，特别是如果考虑基于PKC的药物治疗的话