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）的严重影响是由大约30%的美国成年人患有高血压这一事实所强调的，高血压与发生心力衰竭的风险增加2-3倍有关。HHD的患病率也随着年龄的增长而急剧增加，这使得美国人口老龄化的HHD问题日益严重。因此，寻找有效的HHD治疗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作与心脏中Ca2+/钙调素依赖性激酶II （CaMKII）活性的立即升高有关，这在心脏肥厚和心力衰竭的发展之前。由于已知CaMKII在诱导肥厚和调节兴奋-收缩耦合中发挥重要作用，我们假设高血压导致CaMKII活性升高，进而引发肥厚和心力衰竭的发展。相反，抑制CaMKII可能对减轻HHD的发展有有益的影响。我们建议在HHD发展的三个不同阶段（高血压发病、明显肥厚和心力衰竭）使用CaMKII抑制剂在体内治疗自发性高血压大鼠（SHR）来验证这一假设。特异性Aim-1将确定CaMKII抑制剂治疗对每个HHD阶段CaMKII4B和CaMKII4C亚型活性的影响。特异性Aim-2将检查在减轻肥厚发展和调节心脏功能方面的治疗效果。特异性Aim-3将系统地研究对CaMKII相关的Ca2+处理蛋白的影响，这些蛋白控制心脏兴奋-收缩。作为未来转化研究的第一步，我们还将测量CaMKII及其相关Ca2+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异同将被研究。本初步研究的目的是了解CaMKII4B和CaMKII4C在HHD发展过程中调节结构和功能重塑的分子变化中的作用，并探讨使用CaMKII抑制作为治疗高血压性肥厚、心律失常和心力衰竭的新治疗策略的潜力。高血压是心脏病发生的主要危险因素。本项目拟开展中试研究，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引起的肥厚、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.