Mechanisms and Treatment of Cardiac Arrhythmias

描述（由申请人提供）：心脏肥大是心脏对各种外在和内在刺激的代偿反应。心肌肥厚被认为具有通过减少室壁应力的代偿功能。然而，矛盾的是，心室肥大与心力衰竭和恶性心律失常的风险显著增加有关。抑制核因子NF-？B，最近被研究作为一种可能的治疗方法来治疗心肌肥厚和结果，临床意义是巨大的。我们推测，使用可溶性抑制剂的NF-？B是治疗心肌肥厚的一种有吸引力的治疗手段。另一方面，NF-？在某些条件下，B可以是抗凋亡的和促凋亡的。因此，NF-？心肌肥厚中的B抑制剂仍有待系统研究。受这种核因子抑制剂的不确定性和治疗潜力的影响，我们已经获得了令人惊讶的、令人兴奋的数据，这些数据证明了几种新型有效的可溶性环氧化物水解酶（sEH）抑制剂在心脏肥大中的有益作用。sEH催化环氧二十碳三烯酸（E2）转化为相应的二羟基二十碳三烯酸（DH 2）。内皮素是细胞色素P450表氧化酶的产物，具有与内皮源性超极化因子相似的血管舒张特性。此外，雌二醇抑制NF-？B介导的基因转录。具体来说，我们已经表明，有一个几乎完全解决的心脏肥大的sEH抑制剂独立的抗高血压作用。我们能够证明，在我们的初步研究结果，这些化合物有力地阻止NF-？心肌细胞中的B激活。此外，我们的研究显示了该化合物在预防与心脏肥大相关的心律失常中的有益作用。受这些初步观察的启发，我们的理由是，这些化合物可以被利用来作为一种工具，系统地探测在短期和长期治疗心脏肥大的sEH抑制可能的有益影响，以及研究的机制和参与NF-？心肌肥厚中的B信号通路。因此，该提案的中心目标是使用sEH抑制剂来直接测试新概念，即增强内源性EH可用作预防和逆转心脏肥大的手段，并通过抑制NF-？B激活。

DESCRIPTION (provided by applicant): Cardiac hypertrophy is the heart's compensatory response to a variety of extrinsic and intrinsic stimuli. Cardiac hypertrophy is believed to have a compensatory function by diminishing wall stress. Yet, paradoxically, ventricular hypertrophy is associated with a significant increase in the risk of heart failure and malignant arrhythmia. Inhibition of the nuclear factor, NF-?B, has recently been investigated as one of the possible therapeutic approaches to the treatment of cardiac hypertrophy and the results, and clinical significance promise to be vast. We surmised that the use of soluble inhibitors of NF-?B would present an attractive therapeutic means to treat cardiac hypertrophy. On the other hand, NF-?B can be both anti- and pro-apoptotic in certain conditions. Therefore, the beneficial effects of NF-?B inhibitors in cardiac hypertrophy remain to be systematically investigated. Motivated by the uncertainties, and the therapeutic potential of the inhibitors of this nuclear factor, we have obtained surprising yet, exciting data which demonstrate the beneficial effects of several novel potent soluble epoxide hydrolase (sEH) inhibitors in cardiac hypertrophy. sEH catalizes the conversion of epoxyeicosatrienoic acids (EETs) to form the corresponding dihydroxyeicosatrienoic acids (DHETs). EETs are products of cytochrome P450 epoxygenases that have vasodilatory properties similar to that of endothelium-derived hyperpolarizing factor. In addition, EETs inhibit the activation of NF-?B-mediated gene transcription. Specifically, we have shown that there is an almost complete resolution of cardiac hypertrophy by sEH inhibitors independent of the antihypertensive effects. We were able to demonstrate in our preliminary findings that these compounds potently block the NF-?B activation in cardiac myocytes. Moreover, our study shows a beneficial effect of the compounds in the prevention of cardiac arrhythmias which occur in association with cardiac hypertrophy. Inspired by these initial observations, we reason that these compounds can be exploited to be used as a tool to systematically probe the possible beneficial effects of sEH inhibition in the short- and long-term treatment of cardiac hypertrophy as well as to study the mechanisms and involvement of NF-?B signaling pathway in cardiac hypertrophy. Thus, the central goal of the proposal is to use sEH inhibitors to directly test the novel concept that enhancement of endogenous EETs can be used as a mean to prevent and reverse cardiac hypertrophy and prevent the occurrence of cardiac arrhythmias via inhibition of NF-?B activation.