Qian Yile, Qi Yanyu, Lin Junyi, Zhang Tianyi, Mo Lingjie, Xue Qiupeng, Zheng Nianchang, Niu Yaqin, Dong Xiaoru, Shi Yan, Jiang Yan
Department of Forensic Medicine, School of Basic Medical Sciences, Fudan University, Shanghai, 200032, China.
School of Basic Medical Sciences, Fudan University, Shanghai, 200032, China.
Free Radic Biol Med. 2025 Mar 1;229:237-250. doi: 10.1016/j.freeradbiomed.2025.01.018. Epub 2025 Jan 11.
Chronic ethanol (EtOH) consumption has been widely recognized as a significant contributor to cardiotoxicity. However, no specific treatment is currently available to ameliorate chronic ethanol induced cardiotoxicity. Adiponectin receptor agonist AdipoRon exerts protective effects in multiple organs through alleviating lipotoxicity. Our previous study showed that chronic ethanol consumption increased de novo ceramide synthesis and necroptosis in myocardium. In this study, we investigated the role of AdipoRon on ceramide metabolism and necroptosis in chronic ethanol-treated myocardium. Eight-week-old C57/BL6J mice were fed with a Lieber-Decarli diet containing vehicle or AdipoRon for 12 weeks. Cardiac function, histology and oxidative stress were assessed. We found that chronic ethanol treatment decreased expression of AdipoR2 in myocardium and H9c2 cells, whereas AdipoRon improved cardiac function, reduced myocardium ceramide levels and suppressed necroptosis. By pharmacological interventions, RNA interference and point mutations in AdipoR2, we demonstrated that AdipoRon reduced ceramide levels through PPARα mediated lipid metabolism rather than AdipoR2's ceramidase activity. Using transmission electron microscope and reactive oxygen species (ROS) staining, we showed that chronic ethanol induced myocardium mitochondria damage and mitochondrial reactive oxygen species (mtROS) accumulation. Meanwhile, we found that AdipoRon ameliorated chronic ethanol induced cardiac necroptosis via the SIRT3-SOD2-mtROS pathway. Moreover, C6 ceramide treatment recapitulated chronic ethanol in inducing mtROS and necroptosis, whereas the ceramide synthesis inhibitors myriocin (MYR) and fumonisin B1 (FB1) attenuated chronic ethanol induced mtROS and necroptosis. Collectively, AdipoRon ameliorates chronic ethanol induced cardiac necroptosis by reducing ceramide de novo synthesis and mtROS, which highlights the therapeutic potential of targeting ceramide metabolism and oxidative stress pathways in treating ethanol induced cardiotoxicity.
长期摄入乙醇已被广泛认为是导致心脏毒性的一个重要因素。然而，目前尚无特异性治疗方法可改善慢性乙醇诱导的心脏毒性。脂联素受体激动剂AdipoRon通过减轻脂毒性对多个器官发挥保护作用。我们之前的研究表明，长期摄入乙醇会增加心肌中神经酰胺的从头合成和坏死性凋亡。在本研究中，我们探究了AdipoRon在慢性乙醇处理的心肌中对神经酰胺代谢和坏死性凋亡的作用。将8周龄的C57/BL6J小鼠用含溶剂或AdipoRon的Lieber-Decarli饮食喂养12周。评估心脏功能、组织学和氧化应激。我们发现，慢性乙醇处理降低了心肌和H9c2细胞中AdipoR2的表达，而AdipoRon改善了心脏功能，降低了心肌神经酰胺水平并抑制了坏死性凋亡。通过药理学干预、RNA干扰和AdipoR2中的点突变，我们证明AdipoRon通过PPARα介导的脂质代谢而非AdipoR2的神经酰胺酶活性降低了神经酰胺水平。使用透射电子显微镜和活性氧（ROS）染色，我们表明慢性乙醇诱导心肌线粒体损伤和线粒体活性氧（mtROS）积累。同时，我们发现AdipoRon通过SIRT3-SOD2-mtROS途径改善慢性乙醇诱导的心脏坏死性凋亡。此外，C6神经酰胺处理重现了慢性乙醇诱导mtROS和坏死性凋亡的作用，而神经酰胺合成抑制剂myriocin（MYR）和伏马菌素B1（FB1）减轻了慢性乙醇诱导的mtROS和坏死性凋亡。总的来说，AdipoRon通过减少神经酰胺的从头合成和mtROS改善慢性乙醇诱导的心脏坏死性凋亡，这突出了靶向神经酰胺代谢和氧化应激途径在治疗乙醇诱导的心脏毒性中的治疗潜力。
