Mechanisms and Treatment of Cardiac Arrhythmias

描述（由申请人提供）：心脏肥厚是心脏对各种外在和内在刺激的代偿反应。心肌肥厚被认为通过减少壁应力具有代偿功能。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，最近被研究作为治疗心脏肥厚的可能的治疗方法之一，其结果和临床意义有望是巨大的。我们推测使用可溶性NF-？B将是治疗心脏肥厚的一种有吸引力的治疗手段。另一方面，NF-？B在一定条件下可同时具有抗和促凋亡作用。因此，NF-？B抑制剂在心肌肥厚中的作用仍有待系统研究。由于这种核因子抑制剂的不确定性和治疗潜力，我们获得了令人惊讶但令人兴奋的数据，证明了几种新型有效的可溶性环氧化物水解酶（sEH）抑制剂对心脏肥厚的有益作用。sEH催化环氧二碳三烯酸（EETs）转化为相应的二羟基二碳三烯酸（DHETs）。eet是细胞色素P450环氧合酶的产物，具有类似于内皮源性超极化因子的血管扩张特性。此外，eet抑制NF-？b介导的基因转录。具体来说，我们已经表明，sEH抑制剂几乎完全解决了心脏肥厚，而不依赖于抗高血压作用。我们能够在我们的初步发现中证明这些化合物有效地阻断NF-？心肌细胞B活化。此外，我们的研究表明，化合物在预防与心脏肥厚相关的心律失常方面具有有益作用。受这些初步观察结果的启发，我们认为这些化合物可以作为一种工具来系统地探索sEH抑制在心脏肥厚的短期和长期治疗中可能产生的有益作用，并研究NF-？心肌肥厚的B信号通路。因此，该提案的中心目标是使用sEH抑制剂直接测试新概念，即增强内源性eet可以作为预防和逆转心脏肥厚的手段，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.