Pharmacological inhibition of arachidonate 12-lipoxygenase ameliorates myocardial ischemia-reperfusion injury in multiple species.

Abstract

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.

• Authors: Xiao-Jing Zhang, Xiaolan Liu, Manli Hu, Guo-Jun Zhao, Dating Sun, Xu Cheng, Hui Xiang, Yong-Ping Huang, Rui-Feng Tian, Li-Jun Shen, Jun-Peng Ma, Hai-Ping Wang, Song Tian, Shanyu Gan, Haibo Xu, Rufang Liao, Toujun Zou, Yan-Xiao Ji, Peng Zhang, Jingjing Cai, Zhao V Wang, Guannan Meng, Qingbo Xu, Yibin Wang, Xin-Liang Ma, Peter P Liu, Zan Huang, Lihua Zhu, Zhi-Gang She, Xin Zhang, Lan Bai, Hailong Yang, Zhibing Lu, Hongliang Li
• Journal: Cell metabolism (Cell Metab) Vol. 33 Issue 10 Pg. 2059-2075.e10 (10 05 2021) ISSN: 1932-7420 [Electronic] United States
• PMID: 34536344 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2021 Elsevier Inc. All rights reserved.

Chemical References

• Arachidonate 12-Lipoxygenase

Topics

• Animals
• Arachidonate 12-Lipoxygenase
• Mice
• Myocardial Infarction
• Myocardial Reperfusion Injury (drug therapy)
• Myocytes, Cardiac
• Swine