Darwesh Ahmed M, Fang Liye, Altamimi Tariq R, Jamieson K Lockhart, Bassiouni Wesam, Valencia Robert, Huang Andy, Wang Faqi, Zhang Hao, Ahmed Marawan, Gopal Keshav, Zhang Yongneng, Michelakis Evangelos D, Ussher John R, Edin Matthew L, Zeldin Darryl C, Barakat Khaled, Oudit Gavin Y, Kassiri Zamaneh, Lopaschuk Gary D, Seubert John M
Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, 2-35 Medical Sciences Building, Edmonton, AB, Canada T6G 2H1.
Department of Pharmacology, Faculty of Medicine and Dentistry, University of Alberta, 7-55 Medical Sciences Building, Edmonton, AB, Canada T6G 2H7.
Cardiovasc Res. 2025 Apr 22;121(2):267-282. doi: 10.1093/cvr/cvae252.
Although current clinical therapies following myocardial infarction (MI) have improved patient outcomes, morbidity, and mortality rates, secondary to ischaemic and ischaemia reperfusion (IR) injury remains high. Maintaining mitochondrial quality is essential to limit myocardial damage following cardiac ischaemia and IR injury. The mitochondrial deacetylase sirtuin 3 (SIRT3) plays a pivotal role in regulating mitochondrial function and cardiac energy metabolism. In the current study, we hypothesize that 19,20-epoxydocosapentaenoic acid (19,20-EDP) attenuates cardiac IR injury via stimulating mitochondrial SIRT3.
Ex vivo models of isolated heart perfusions were performed in C57BL/6 mice to assess the effect of 19,20-EDP on cardiac function and energy metabolism following IR injury. In vivo permanent occlusion of the left anterior descending coronary artery was performed to induce MI; mice were administered 19,20-EDP with or without the SIRT3 selective inhibitor 3-TYP. Mitochondrial SIRT3 targets and respiration were assessed in human left ventricular tissues obtained from individuals with ischaemic heart disease (IHD) and compared to non-failing controls (NFCs). Binding affinity of 19,20-EDP to human SIRT3 was assessed using molecular modelling and fluorescence thermal shift assay. Results demonstrated that hearts treated with 19,20-EDP had improved post-ischaemic cardiac function, better glucose oxidation rates, and enhanced cardiac efficiency. The cardioprotective effects were associated with enhanced mitochondrial SIRT3 activity. Interestingly, treatment with 19,20-EDP markedly improved mitochondrial respiration and SIRT3 activity in human left ventricle (LV) fibres with IHD compared to NFC. Moreover, 19,20-EDP was found to bind to the human SIRT3 protein enhancing the NAD+-complex stabilization leading to improved SIRT3 activity. Importantly, the beneficial effects of 19,20-EDP were abolished by SIRT3 inhibition or using the S149A mutant SIRT3.
These data demonstrate that 19,20-EDP-mediated cardioprotective mechanisms against ischaemia and IR injury involve mitochondrial SIRT3, resulting in improved cardiac efficiency.
尽管目前心肌梗死（MI）后的临床治疗已改善了患者的预后、发病率和死亡率，但继发于缺血及缺血再灌注（IR）损伤的情况仍然很严重。维持线粒体质量对于限制心脏缺血和IR损伤后的心肌损伤至关重要。线粒体去乙酰化酶沉默调节蛋白3（SIRT3）在调节线粒体功能和心脏能量代谢中起关键作用。在本研究中，我们假设19,20-环氧二十二碳五烯酸（19,20-EDP）通过刺激线粒体SIRT3减轻心脏IR损伤。
在C57BL/6小鼠中进行离体心脏灌注的体外模型，以评估19,20-EDP对IR损伤后心脏功能和能量代谢的影响。在体内进行左冠状动脉前降支永久性闭塞以诱导MI；给小鼠施用19,20-EDP，同时给予或不给予SIRT3选择性抑制剂3-TYP。在从缺血性心脏病（IHD）患者获得的人左心室组织中评估线粒体SIRT3靶点和呼吸作用，并与非衰竭对照（NFC）进行比较。使用分子建模和荧光热位移分析评估19,20-EDP与人SIRT3的结合亲和力。结果表明，用19,20-EDP处理的心脏缺血后心脏功能得到改善，葡萄糖氧化率更高，心脏效率增强。心脏保护作用与线粒体SIRT3活性增强有关。有趣的是，与NFC相比，用19,20-EDP治疗可显著改善IHD患者人左心室（LV）纤维中的线粒体呼吸和SIRT3活性。此外，发现19,20-EDP与人SIRT3蛋白结合，增强了NAD +复合物的稳定性，从而提高了SIRT3活性。重要的是，SIRT3抑制或使用S149A突变体SIRT3消除了19,20-EDP的有益作用。
这些数据表明，19,20-EDP介导的针对缺血和IR损伤的心脏保护机制涉及线粒体SIRT3，从而提高了心脏效率。
