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，已被证明在各种疾病模型中发挥有效的抗炎作用。因此，我们的小组能够证明，硝基-9-顺式-十八碳烯酸（OA-NO2）是大量产生的，减少梗死面积和保留左心室功能在心肌再灌注，并表现出强大的抗纤维化作用的心房和心室水平。该领域正在进行的研究表明，饮食调整可以将这些化合物增加到治疗水平，而10-硝基-9（E）-十八碳-9-烯酸（CXA-10）的临床1期和2a期研究，OA-NO2的10-异构体显示出有利的副作用特征和令人鼓舞的初步结果。为了进一步了解它们的治疗潜力，目前的建议旨在确定通过膳食补充共轭亚油酸内源性产生NO2-FA的治疗作用（（9 Z，11 E）-cLA和（10 E，12 Z）-cLA的外消旋混合物）和亚硝酸盐的作用，以及外源施用的合成硝化油酸（OA-NO2）在不同的，临床上有意义的，急性心肌梗死的分期在初步研究中，OA-NO2在心肌缺血两分钟后有效地抑制了室颤的诱导，提出了OA-NO2是否可以作为梗死相关心脏性猝死的预防策略的问题，特别是考虑到饮食调整血浆水平的可能性。观察将扩展到研究饮食和合成方法对1a相和1b相室性心动过速的影响。最后，将在永久性LAD结扎的3周模型中评价NO2-FA对心室纤维化重构的长期影响。

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.