Lipoxygenase drives lipidomic and metabolic reprogramming in ischemic heart failure

Background: 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 inHF. There is no consensus on metabolic and lipidomic signatures that influence structure, function, and survival in HF. Herewe use genetic knock outmodel to delineate lipidomic, and meta- bolic changes to describe the role of lipoxygenase in advancing ischemic HF driven by leukocyte activation with signs of non-resolving inflammation. Bioactive lipids andmetabolites 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 andmeta- bolic reprogramming in HF. Materials and methods: 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 cardiacpathophysiology in acute andchronicHF. For this,we quantitated sys- temicmetabolic changes and lipidomic profiling in infarcted heart tissue with obvious structural remodeling and cardiac dysfunction progressing fromacute to chronic HF in the survival cohort. Results: After MI, lipoxygenase-derived specialized pro-resolving mediators were quantitated and showed lipoxygenase-deficient mice (12/15LOX−/−) biosynthesize epoxyeicosatrienoic acid (EETs; cypoxins) to facili- tate cardiac healing. Lipoxygenase-deficientmice reduced diabetes risk biomarker 2-aminoadipic acidwith pro- found alterations of plasma metabolic signaling of hexoses, amino acids, biogenic amines, acylcarnitines, glycerophospholipids, and sphingolipids in acute HF, thereby improved survival. Conclusion: Specific lipoxygenase deletion alters lipidomic and metabolic signatures, with modified leukocyte profiling that delayed HF progression and improved survival. Future studies arewarranted to define themolec- ular network of lipidome and metabolome in acute and chronic HF patients.