CaMKII Inhibition as a New Therapeutic Strategy for Treating Hypertension-induced

描述(由申请人提供)：高血压引起的心脏病(HHD，即心脏肥厚、心力衰竭)的严重影响因以下事实而得到强调：约30%的美国成年人患有高血压，高血压与发生心力衰竭的风险高出2-3倍。HHD的患病率也随着老龄化而急剧增加，这导致了美国人口老龄化带来的HHD问题日益严重。因此，寻找治疗HHD的有效方法具有重要的临床意义和紧迫性。最近，我们发现高血压的发生与心脏内钙/钙调蛋白依赖性激酶II(CaMKII)活性的即刻升高有关，这种活性先于心肌肥厚和心力衰竭的发展。由于CaMKII在诱导肥厚和调节兴奋-收缩偶联中起重要作用，我们假设高血压导致CaMKII活性升高，进而触发肥厚和心力衰竭的发展。相反，抑制CaMKII可能在缓解HHD的发展方面具有有利的作用。我们建议通过使用CaMKII抑制剂在体内治疗自发性高血压大鼠(SHR)HHD发展的三个不同阶段来验证这一假设：高血压发作、显性肥厚和心力衰竭。特定的AIM-1将确定CaMKII抑制剂处理对每个HHD阶段CaMKII4B和CaMKII4C亚型活性的影响。特定的AIM-2将检查在缓解肥厚发展和调节心脏功能方面的治疗效果。SPICAL-AIM-3将系统地研究控制心脏兴奋收缩的CaMKII相关钙处理蛋白的作用。作为未来翻译研究的第一步，我们还将测量CaMKII及其相关的钙处理分子在人类衰竭心脏中的变化。我们将研究自发性高血压和人类心脏衰竭之间的异同。这项先导性研究的目的是了解CaMKII4B和CaMKII4C在调节高血压发育过程中结构和功能重构的分子变化中的作用，并探讨使用CaMKII抑制作为治疗高血压引起的肥厚、心律失常和心力衰竭的新治疗策略的可能性。公共卫生相关性高血压是发展心脏病的主要危险因素。该项目建议进行一项初步研究，以探索在心脏抑制CaMKII作为治疗高血压性心脏病的新策略的可行性和潜力。我们将首先使用模拟人类临床阶段的动物模型(自发性高血压大鼠)进行初步研究。长期目标是开发有效的治疗高血压引起的肥厚、心律失常和人类患者心力衰竭的方法。

DESCRIPTION (provided by applicant): The severe impact of hypertension-induced heart disease (HHD, i.e. cardiac hypertrophy, heart failure) is underscored by the fact that about 30% of the US adult population has high blood pressure, and hypertension is associated with a 2-3 fold higher risk for developing heart failure. The prevalence of HHD also drastically increases with aging, which poses a growing HHD problem with the aging population in US. Hence finding effective treatments for HHD is of great clinical importance and urgency. Recently, we discovered that the onset of hypertension was associated with an immediate elevation of Ca2+/calmodulin-dependent kinase II (CaMKII) activity in the heart which preceded the development of cardiac hypertrophy and heart failure. Since CaMKII is known to play significant role in inducing hypertrophy and modulating excitation-contraction coupling, we hypothesize that hypertension causes elevation of CaMKII activity which, in turn, triggers the development of hypertrophy and heart failure. Conversely, CaMKII inhibition may have beneficial effects on mitigating the HHD development. We propose to test this hypothesis by using CaMKII inhibitor to treat the spontaneously hypertensive rat (SHR) in vivo at three distinct stages during HHD development: onset of hypertension, overt hypertrophy, and heart failure. Specific Aim-1 will establish the effects of CaMKII inhibitor treatment on the CaMKII4B and CaMKII4C isoform's activity at each HHD stage. Specific Aim-2 will examine the treatment effects on mitigating hypertrophy development and modulating heart function. Specific Aim-3 will systematically study the effects on CaMKII related Ca2+ handling proteins that control cardiac excitation-contraction. As the first step towards future translational research, we will also measure changes in CaMKII and its related Ca2+ handling molecules in human failing hearts. The similarities and differences between SHR and human failing hearts will be examined. The goal of this pilot study is to understand the effects of CaMKII4B and CaMKII4C on regulating the molecular changes that underlie the structural and functional remodeling during HHD development, and to investigate the potential of using CaMKII inhibition as a new therapeutic strategy for treating hypertension-induced hypertrophy, arrhythmias and heart failure. PUBLIC HEALTH RELEVANCE High blood pressure is a major risk factor for developing heart diseases. This project proposes to conduct a pilot study to explore the feasibility and the potential of inhibiting CaMKII in the heart as a new strategy for treating hypertensive heart disease. We will first conduct the pilot study using an animal model (spontaneously hypertensive rat) that mimics human clinical stages. The long term goal is to develop effective treatment for hypertension-induced hypertrophy, arrhythmias, and heart failure in human patients.