Myocardial ischemia-reperfusion (MIR) injury is a major cause of adverse outcomes of revascularization after myocardial infarction. To identify the fundamental regulator of reperfusion injury, we performed metabolomics profiling in plasma of individuals before and after revascularization and identified a marked accumulation of arachidonate 12-lipoxygenase (ALOX12)-dependent 12-HETE following revascularization. The potent induction of 12-HETE proceeded by reperfusion was conserved in post-MIR in mice, pigs, and monkeys. While genetic inhibition of Alox12 protected mouse hearts from reperfusion injury and remodeling, Alox12 overexpression exacerbated MIR injury. Remarkably, pharmacological inhibition of ALOX12 significantly reduced cardiac injury in mice, pigs, and monkeys. Unexpectedly, ALOX12 promotes cardiomyocyte injury beyond its enzymatic activity and production of 12-HETE but also by its suppression of AMPK activity via a direct interaction with its upstream kinase TAK1. Taken together, our study demonstrates that ALOX12 is a novel AMPK upstream regulator in the post-MIR heart and that it represents a conserved therapeutic target for the treatment of myocardial reperfusion injury.

心肌缺血再灌注（MIR）损伤是心肌梗死后血运重建不良后果的主要原因。为了确定再灌注损伤的基本调节因子，我们在血运重建前后对个体血浆进行了代谢组学分析，并确定了血运重建后花生四烯酸 12-脂氧合酶 (ALOX12) 依赖性 12-HETE 的显着积累。通过再灌注进行的 12-HETE 的有效诱导在小鼠、猪和猴子的 MIR 后保留。虽然Alox12的基因抑制保护小鼠心脏免受再灌注损伤和重塑，但 Alox12过表达加剧了 MIR 损伤。值得注意的是，ALOX12 的药理学抑制显着降低了小鼠、猪和猴子的心脏损伤。出乎意料的是，ALOX12 促进心肌细胞损伤的不仅仅是其酶活性和 12-HETE 的产生，而且还通过与其上游激酶 TAK1 的直接相互作用抑制 AMPK 活性。总之，我们的研究表明，ALOX12 是 MIR 后心脏中一种新型的 AMPK 上游调节剂，它代表了治疗心肌再灌注损伤的保守治疗靶点。