Division of Cardiovascular Disease, Department of Medicine, The University of Alabama at Birmingham, AL, United States.
Division of Cardiovascular Disease, Department of Medicine, The University of Alabama at Birmingham, AL, United States.
Metabolism. 2019 Jul;96:22-32. doi: 10.1016/j.metabol.2019.04.011. Epub 2019 Apr 15.
After myocardial infarction (MI), delayed progression or reversal of cardiac remodeling is a prime target to limit advanced chronic heart failure (HF). However, the temporal kinetics of lipidomic and systemic metabolic signaling is unclear in HF. There is no consensus on metabolic and lipidomic signatures that influence structure, function, and survival in HF. Here we use genetic knock out model to delineate lipidomic, and metabolic changes to describe the role of lipoxygenase in advancing ischemic HF driven by leukocyte activation with signs of non-resolving inflammation. Bioactive lipids and metabolites are implicated in acute and chronic HF, and the goal of this study was to define the role of lipoxygenase in temporal kinetics of lipidomic and metabolic reprogramming in HF.
To address this question, we used a permanent coronary ligation mouse model which showed profound metabolic and lipidomic reprogramming in acute HF. Additionally, we defined the lipoxygenase-mediated changes in cardiac pathophysiology in acute and chronic HF. For this, we quantitated systemic metabolic changes and lipidomic profiling in infarcted heart tissue with obvious structural remodeling and cardiac dysfunction progressing from acute to chronic HF in the survival cohort.
After MI, lipoxygenase-derived specialized pro-resolving mediators were quantitated and showed lipoxygenase-deficient mice (12/15LOX) biosynthesize epoxyeicosatrienoic acid (EETs; cypoxins) to facilitate cardiac healing. Lipoxygenase-deficient mice reduced diabetes risk biomarker 2-aminoadipic acid with profound alterations of plasma metabolic signaling of hexoses, amino acids, biogenic amines, acylcarnitines, glycerophospholipids, and sphingolipids in acute HF, thereby improved survival.
Specific lipoxygenase deletion alters lipidomic and metabolic signatures, with modified leukocyte profiling that delayed HF progression and improved survival. Future studies are warranted to define the molecular network of lipidome and metabolome in acute and chronic HF patients.
心肌梗死（MI）后，心脏重构的延迟进展或逆转是限制晚期慢性心力衰竭（HF）的主要靶点。然而，HF 中脂质组学和全身代谢信号的时间动力学尚不清楚。在 HF 中，没有关于影响结构、功能和生存的代谢和脂质组学特征的共识。在这里，我们使用基因敲除模型来描绘脂质组学和代谢变化，以描述白细胞激活驱动的缺血性 HF 中脂氧合酶的作用，其特征是存在非解决性炎症。生物活性脂质和代谢物与急性和慢性 HF 有关，本研究的目的是定义脂氧合酶在 HF 中脂质组学和代谢重编程的时间动力学中的作用。
为了解决这个问题，我们使用了一种永久性冠状动脉结扎小鼠模型，该模型在急性 HF 中表现出明显的代谢和脂质组学重编程。此外，我们定义了脂氧合酶在急性和慢性 HF 中心脏病理生理学中的介导变化。为此，我们在存活队列中定量了梗死心脏组织中的系统代谢变化和脂质组学谱，这些组织具有明显的结构重构和心功能障碍，从急性 HF 进展为慢性 HF。
在 MI 后，定量了脂氧合酶衍生的特殊促解决介质，并且发现脂氧合酶缺陷型小鼠（12/15LOX）生物合成环氧二十碳三烯酸（EETs；环氧化物）以促进心脏愈合。脂氧合酶缺陷型小鼠减少了糖尿病风险生物标志物 2-氨基己二酸，同时急性 HF 中血浆代谢信号的葡萄糖、氨基酸、生物胺、酰基辅酶 A、甘油磷脂和神经酰胺显著改变，从而提高了生存率。
特定的脂氧合酶缺失改变了脂质组学和代谢特征，并改变了白细胞表型，从而延缓了 HF 的进展并提高了生存率。未来的研究需要定义急性和慢性 HF 患者脂质组学和代谢组学的分子网络。
