Anti-arrhythmic and anti-fibrotic effects of nitrated fatty acids in myocardial remodeling.

硝化脂肪酸（NO2-FA）是内源性产生的信号介质，已被证明在多种疾病模型中发挥有效的抗炎作用。因此，我们的研究小组能够证明大量生成硝基9-顺式十八烯酸（OA-NO2），在心肌再灌注期间减少梗死面积并保持左心室功能，并在心房和心室水平上显示出有效的抗纤维化作用。该领域正在进行的研究表明，饮食改变可以将这些化合物提高到治疗水平，而10-硝基-9(E)-十八烷基-9-烯酸（CXA-10）的临床1期和2a期研究显示，OA-NO2的10-异构体具有良好的副作用和令人鼓舞的初步结果。为了进一步了解它们的治疗潜力，本研究旨在确定通过膳食补充共轭亚油酸(（9Z,11E)-cLA和(10E,12Z)-cLA的外消泡混合物）和亚硝酸盐内源性生成NO2-FA的治疗效果，以及外源性应用合成硝化油酸（OA-NO2）在不同临床意义的急性心肌梗死阶段的作用。在初步研究中，OA-NO2有效抑制心肌缺血2分钟后心室颤动的诱导性，这提出了OA-NO2是否可以作为梗死相关心源性猝死的预防策略的问题，特别是考虑到饮食改变血浆水平的可能性。我们将进一步研究膳食和合成方法对1a期和1b期室性心动过速的影响。最后，将在为期3周的永久性LAD结扎模型中评估NO2-FA对心室纤维化重塑的长期影响。

Nitrated fatty acids (NO2-FA) are endogenously generated signalling mediators that have been shown to exert potent anti-inflammatory effects in a variety of disease models. Thus, our group was able to demonstrate that nitro-9-cis-octadecenoic acid (OA-NO2) is abundantly generated, reduces infarct size and preserves left ventricular function during myocardial reperfusion and exhibits potent anti-fibrotic effects on the atrial and ventricular level. Ongoing research in the field revealed that dietary modifications can increase these compounds to therapeutic levels, while clinical phase 1 and 2a studies with 10-nitro-9(E)-octadec-9-enoic acid (CXA-10), the 10-isomer of OA-NO2 show a favourable side effect profile and encouraging preliminary results. In an effort to further our understanding of their therapeutic potential the current proposal aims to define the therapeutic effects of endogenous generation of NO2-FA by dietary supplementation with conjugated linoleic acid (racemic mixture of (9Z,11E)-cLA and (10E,12Z)-cLA) and nitrite and the effects of exogenously applied synthetic nitrated oleic acids (OA-NO2) throughout different, clinically meaningful, stages of acute myocardial infarction. In preliminary studies OA-NO2 potently suppressed inducibility of ventricular fibrillation after two minutes of myocardial ischemia, raising the question whether OA-NO2 could emerge as preventive strategy for infarct-related sudden cardiac death, particularly given the possibility for dietary modification of plasma levels. The observations will be extended to investigate the effects of both the dietary and synthetic approach on phase 1a and phase 1b ventricular tachycardias. Finally, long-term effects of NO2-FA on ventricular fibrotic remodeling will be evaluated in a 3-week model of permanent LAD ligation.