Calmodulin kinase II inhibition as novel molecular treatment of hypertension

描述(由申请人提供)： 多功能的钙/钙调蛋白依赖的激酶II(CaMKII)的功能在血管系统中仍然知之甚少。我们的数据表明，CaMKII在调节血管紧张素-II(Ang-II)高血压的血压升高中起着重要作用。因此，抑制CaMKII可能是治疗高血压的一种有效的新方法。目前通过退伍军人管理局接受医疗保健的退伍军人中，近50%的人被诊断为高血压。与这种诊断相关的平均治疗费用估计为每位退伍军人每年6000美元。尽管如此，约30%患有高血压的退伍军人目前没有达到目标血压(BP)。我们的长期目标是帮助开发可用于临床治疗高血压的选择性CaMKII抑制剂。作为实现这一目标的下一步， 本应用的目的是阐明CaMKII在已建立的高血压模型中的功能。中心假说是，血管平滑肌细胞中的CaMKII活性通过增加细胞内钙离子从而调节血压来调节血管张力。我们的假设是基于在我们的新的活体小鼠模型中获得的强大的初步数据，在该模型中，有效和特定的内源性CaMKIIN抑制剂CaMKIIN在平滑肌细胞中选择性地过表达。我们的TG SM HA-CaMKIIN小鼠在Ang-II诱导的高血压中表现出显著的降压作用。这项研究的基本原理是，一旦我们了解了CaMKII是如何调节细胞内钙离子从而影响血管平滑肌细胞收缩和血压的，我们就已经迈出了关键的第一步，以评估其作为治疗高血压药物开发的新分子靶点的潜力。在强大的初步数据的指导下，中心假设将在两个具体目标中进行检验：1)确定 在已建立的高血压模型中，血管平滑肌细胞中CaMKII抑制对血压的影响；2)：确定CaMKII如何控制血管平滑肌细胞内的钙负荷。在第一个目的中，将使用新的体内模型来测试CaMKII激活是否是三种血压模型中的共同途径，以及CaMKII的抑制是否足以消除血压的升高。在目标2中，我们将确定CaMKII调控血管平滑肌细胞内钙离子的机制。这种方法是创新的，因为它使用了新的活体模型和特定的工具来剖析CaMKII信号。这项拟议的研究意义重大，因为它有望通过将CaMKII定义为控制细胞内钙离子和血管紧张性的新分子靶点来推动该领域的发展。最终，这些知识可能允许开发新的高血压治疗策略，这将使我们的退伍军人受益。

DESCRIPTION (provided by applicant): The function of the multifunctional Ca2+/calmodulin-dependent kinase II (CaMKII) remains poorly understood in the vasculature. Our data suggest that CaMKII is instrumental in mediating blood pressure increases in Angiotensin-II (Ang-II) hypertension. Thus, CaMKII inhibition may be a potent novel approach to treat high blood pressure. Almost 50% of the veterans that are currently receiving health care through the VA carry the diagnosis of hypertension. The average treatment cost associated with this diagnosis has been estimated at $6,000 per veteran annually. Nonetheless, about 30% of veterans with hypertension currently do not reach the target blood pressure (BP). Our long-term goal is to help develop selective CaMKII inhibitors that can be used clinically for the treatment of hypertension. As a next step toward this goal, the objective of this application is to delineate the function of CaMKII in established models of hypertension. The central hypothesis is that CaMKII activity in vascular smooth muscle cells regulates vascular tone by increasing intracellular Ca2+ and thereby BP. Our hypothesis is based on strong preliminary data obtained in our novel in vivo mouse model in which the potent and specific endogenous CaMKII inhibitor CaMKIIN is selectively overexpressed in smooth muscle cells. Our Tg SM HA-CaMKIIN mice exhibit significantly decreased blood pressure in Ang-II-induced hypertension. The rationale for the proposed studies is that, once we understand how CaMKII regulates intracellular Ca2+ and thereby affects vascular smooth muscle cell contraction and blood pressure, we will have made a critical first step towards assessing its potential as a new molecular target for the development of drugs to treat hypertension. Guided by strong preliminary data, the central hypothesis will be tested in two specific aims: 1) Identify the effect that CaMKII inhibition in vascular smooth muscle cells has on blood pressure in established models of hypertension, 2): Identify how CaMKII controls the intracellular Ca2+ load of vascular smooth muscle cells. In the first aim, the novel in vivo model will be used to test whether CaMKII activation is a common pathway in three blood pressure models and if CaMKII inhibition is sufficient to abrogate the BP increases. Under aim 2, we will define the mechanisms through which CaMKII controls intracellular intracellular Ca2+ in vascular smooth muscle cells. The approach is innovative because of its use of novel in vivo models and specific tools to dissect CaMKII signaling. The proposed research is significant because it is expected to advance the field by defining CaMKII as a novel molecular target that controls intracellular Ca2+ and vascular tone. Ultimately, such knowledge may allow for the development of new therapeutic strategies in hypertension that will benefit our veterans.