杂志名称：Free Radical Biology and Medicine
影响因子：7.1
文章题目：AdipoRon ameliorates chronic ethanol induced cardiac necroptosis by reducing ceramide mediated mtROS
DOI: https://doi.org/10.1016/j.freeradbiomed.2025.01.018
第一作者：Yile Qian, Yanyu Qi, Junyi Lin, Tianyi Zhang, Lingjie Mo, Qiupeng Xue, Nianchang Zheng, Yaqin Niu, Xiaoru Dong, Yan Shi, Yan Jiang
作者单位：
复旦大学基础医学学院
复旦大学基础医学科学学院
中国最高人民检察院法证科学与信息技术研究中心
法医学科学院上海法医学重点实验室
引用YOBIBIO产品：
U96-1696E  Mouse Acrp30/Adiponectin ELISA Kit
U96-5379E  Mouse CK-MB ELISA Kit
U96-3334E  Mouse NT-proBNP ELISA kit

文章摘要：
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.

慢性乙醇 （EtOH） 消耗已被广泛认为是导致心脏毒性的重要因素。然而，目前没有特定的治疗方法可用于改善慢性乙醇引起的心脏毒性。脂联素受体激动剂 AdipoRon 通过减轻脂毒性在多个器官中发挥保护作用。我们之前的研究表明，长期饮用乙醇会增加心肌神经酰胺的新头合成和坏死性凋亡。在这项研究中，我们调查了 AdipoRon 对慢性乙醇治疗心肌神经酰胺代谢和坏死性凋亡的作用。8 周龄 C57/BL6J 小鼠用含有载体或 AdipoRon 的 Lieber-Decarli 饮食喂养 12 周。评估了心脏功能、组织学和氧化应激。我们发现长期乙醇治疗降低了心肌和 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坏死性凋亡。通过药物干预、RNA 干扰和 AdipoR2 中的点突变，我们证明 AdipoRon 通过 PPARα 介导的脂质代谢而不是 AdipoR2 的神经酰胺酶活性降低神经酰胺水平。使用透射电子显微镜和活性氧 （ROS） 染色，我们发现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 通路改善慢性乙醇诱导的心脏坏死性凋亡。此外，C6 神经酰胺处理概括了慢性乙醇诱导 mtROS 和坏死性凋亡的作用，而神经酰胺合成抑制剂肉豆蔻素 （MYR） 和伏马菌素 B1 （FB1） 减弱了慢性乙醇诱导的 mtROS 和坏死性凋亡。 总的来说，AdipoRon 通过减少神经酰胺从头合成和 mtROS 来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方面的治疗潜力。