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药物抑制花生四烯酸12-脂氧合酶可改善多种物种的心肌缺血再灌注损伤
作者:小柯机器人 发布时间:2021/9/24 13:36:09

武汉大学李红良等研究人员合作发现,药物抑制花生四烯酸12-脂氧合酶可改善多种物种的心肌缺血再灌注损伤。相关论文于2021年9月17日在线发表在《细胞—代谢》杂志上。

为了确定再灌注损伤的基本调节因素,研究人员对再灌注前后的个人血浆进行了代谢组学分析,发现再灌注后花生四烯酸12-脂氧合酶(ALOX12)依赖的12-HETE明显积累。在小鼠、猪和猴子的心肌缺血再灌注(MIR)后,再灌注所产生的12-HETE强效诱导作用是保守的。虽然Alox12的遗传抑制保护小鼠心脏免受再灌注损伤和重塑,但Alox12的过度表达却加剧了MIR的损伤。

值得注意的是,对ALOX12的药理抑制明显减少了小鼠、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原因不仅仅是它的酶活性和12-HETE的产生,还因为它通过与其上游激酶TAK1的直接相互作用抑制了AMPK的活性。

总之,这项研究表明,ALOX12是MIR后心脏的一个新型AMPK上游调节因子,它是治疗心肌再灌注损伤的一个保守的治疗靶标。

据了解,MIR损伤是导致心肌梗死后血管重建不良后果的主要原因。

附:英文原文

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

Author: 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

Issue&Volume: 2021-09-17

Abstract: Myocardial ischemia-reperfusion (MIR) injury is a major cause of adverse outcomesof revascularization after myocardial infarction. To identify the fundamental regulatorof reperfusion injury, we performed metabolomics profiling in plasma of individualsbefore and after revascularization and identified a marked accumulation of arachidonate12-lipoxygenase (ALOX12)-dependent 12-HETE following revascularization. The potentinduction 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 ofALOX12 significantly reduced cardiac injury in mice, pigs, and monkeys. Unexpectedly,ALOX12 promotes cardiomyocyte injury beyond its enzymatic activity and productionof 12-HETE but also by its suppression of AMPK activity via a direct interaction withits upstream kinase TAK1. Taken together, our study demonstrates that ALOX12 is anovel AMPK upstream regulator in the post-MIR heart and that it represents a conservedtherapeutic target for the treatment of myocardial reperfusion injury.

DOI: 10.1016/j.cmet.2021.08.014

Source: https://www.cell.com/cell-metabolism/fulltext/S1550-4131(21)00377-6

期刊信息

Cell Metabolism:《细胞—代谢》,创刊于2005年。隶属于细胞出版社,最新IF:22.415
官方网址:https://www.cell.com/cell-metabolism/home
投稿链接:https://www.editorialmanager.com/cell-metabolism/default.aspx