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

描述（由申请人提供）：高血压诱导的心脏病（HHD，即心脏肥大、心力衰竭）的严重影响由以下事实强调：约30%的美国成年人群患有高血压，高血压与发生心力衰竭的风险高2-3倍相关。HHD的患病率也随着老龄化而急剧增加，这在美国随着人口老龄化而造成日益严重的HHD问题。因此，寻找有效的治疗HHD具有重要的临床意义和紧迫性。最近，我们发现高血压的发病与心脏中的Ca 2 +/钙调素依赖性激酶II（CaMKII）活性的立即升高相关，该升高先于心脏肥大和心力衰竭的发展。由于已知CaMKII在诱导肥大和调节兴奋-收缩偶联中起重要作用，我们假设高血压导致CaMKII活性升高，这反过来又触发肥大和心力衰竭的发展。相反，CaMKII抑制可能对减轻HHD发展具有有益作用。我们建议使用CaMKII抑制剂治疗自发性高血压大鼠（SHR）在体内HHD发展过程中的三个不同阶段：高血压，明显肥大和心力衰竭的发病，以测试这一假设。具体目标-1将确定CaMKII抑制剂处理对每个HHD阶段的CaMKII 4 B和CaMKII 4C亚型活性的影响。具体目标-2将检查治疗对减轻肥大发展和调节心脏功能的影响。Specific Aim-3将系统地研究对控制心脏兴奋-收缩的CaMKII相关Ca 2+处理蛋白的影响。作为未来转化研究的第一步，我们还将测量CaMKII及其相关Ca 2+处理分子在人类衰竭心脏中的变化。SHR和人类衰竭心脏之间的相似性和差异将被检查。这项初步研究的目的是了解CaMKII 4 B和CaMKII 4C对调节HHD发展过程中结构和功能重塑的分子变化的影响，并研究使用CaMKII抑制作为治疗高血压诱导的肥大，心律失常和心力衰竭的新治疗策略的潜力。高血压是导致心脏病的主要危险因素。本项目拟开展一项试点研究，探索抑制心脏CaMKII作为治疗高血压性心脏病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诱导的肥大，心律失常和心力衰竭的人类患者。

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.