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

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

  • Cell Metab. 2021 Oct 5;33(10):2059-2075.e10. doi: 10.1016/j.cmet.2021.08.014.
Xiao-Jing Zhang 1,  Xiaolan Liu 2,  Manli Hu 2,  Guo-Jun Zhao 1,  Dating Sun 1,  Xu Cheng 1,  Hui Xiang 1,  Yong-Ping Huang 3,  Rui-Feng Tian 1,  Li-Jun Shen 1,  Jun-Peng Ma 1,  Hai-Ping Wang 1,  Song Tian 1,  Shanyu Gan 1,  Haibo Xu 4,  Rufang Liao 4,  Toujun Zou 1,  Yan-Xiao Ji 1,  Peng Zhang 1,  Jingjing Cai 5,  Zhao V Wang 6,  Guannan Meng 7,  Qingbo Xu 8,  Yibin Wang 9,  Xin-Liang Ma 10,  Peter P Liu 11,  Zan Huang 12,  Lihua Zhu 1,  Zhi-Gang She 1,  Xin Zhang 13,  Lan Bai 14,  Hailong Yang 15,  Zhibing Lu 16,  Hongliang Li 17
Affiliations

Affiliations

  • 1 Department of Cardiology, Renmin Hospital, School of Basic Medical Science, Wuhan University, Wuhan 430071, China; Institute of Model Animal of Wuhan University, Wuhan 430071, China.
  • 2 Institute of Model Animal of Wuhan University, Wuhan 430071, China; Medical Science Research Center, Zhongnan Hospital of Wuhan University, Wuhan 430071, China.
  • 3 Institute of Model Animal of Wuhan University, Wuhan 430071, China; College of Life Sciences, Wuhan University, Wuhan 430072, China.
  • 4 Department of Radiology, Zhongnan Hospital of Wuhan University, Wuhan 430071, China.
  • 5 Department of Cardiology, Third Xiangya Hospital, Central South University, Changsha 410013, China.
  • 6 Division of Cardiology, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
  • 7 Department of Cardiology, Renmin Hospital, School of Basic Medical Science, Wuhan University, Wuhan 430071, China.
  • 8 Centre for Clinic Pharmacology, William Harvey Research Institute, Queen Mary University of London, London, UK.
  • 9 Department of Anesthesiology, Cardiovascular Research Laboratories, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
  • 10 Department of Emergency Medicine, Thomas Jefferson University, Philadelphia, PA 19004, USA.
  • 11 Division of Cardiology, University of Ottawa Heart Institute, Ottawa, ON K1Y 4W7, Canada.
  • 12 College of Life Sciences, Wuhan University, Wuhan 430072, China.
  • 13 Gannan Institute of Translational Medicine, Ganzhou 341000, China.
  • 14 Department of Cardiology, Renmin Hospital, School of Basic Medical Science, Wuhan University, Wuhan 430071, China; Institute of Model Animal of Wuhan University, Wuhan 430071, China. Electronic address: bailan@whu.edu.cn.
  • 15 Department of Cardiology, Renmin Hospital, School of Basic Medical Science, Wuhan University, Wuhan 430071, China; Institute of Model Animal of Wuhan University, Wuhan 430071, China. Electronic address: yhlslh@whu.edu.cn.
  • 16 Department of Cardiology, Zhongnan Hospital of Wuhan University, Wuhan 430060, China. Electronic address: luzhibing222@163.com.
  • 17 Department of Cardiology, Renmin Hospital, School of Basic Medical Science, Wuhan University, Wuhan 430071, China; Institute of Model Animal of Wuhan University, Wuhan 430071, China; Medical Science Research Center, Zhongnan Hospital of Wuhan University, Wuhan 430071, China. Electronic address: lihl@whu.edu.cn.
PMID: 34536344 DOI: 10.1016/j.cmet.2021.08.014
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.

Keywords

12-HETE; ALOX12; AMPK; arachidonic acid; myocardial ischemia-reperfusion injury.

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