雜志名稱：Free Radical Biology and Medicine
影響因子：7.1
文章題目：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
作者單位：
復旦大學基礎醫(yī)學學院
復旦大學基礎醫(yī)學科學學院
中國最高人民檢察院法證科學與信息技術研究中心
法醫(yī)學科學院上海法醫(yī)學重點實驗室
引用YOBIBIO產品：
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） 消耗已被廣泛認為是導致心臟毒性的重要因素。然而，目前沒有特定的治療方法可用于改善慢性乙醇引起的心臟毒性。脂聯(lián)素受體激動劑 AdipoRon 通過減輕脂毒性在多個器官中發(fā)揮保護作用。我們之前的研究表明，長期飲用乙醇會增加心肌神經酰胺的新頭合成和壞死性凋亡。在這項研究中，我們調查了 AdipoRon 對慢性乙醇治療心肌神經酰胺代謝和壞死性凋亡的作用。8 周齡 C57/BL6J 小鼠用含有載體或 AdipoRon 的 Lieber-Decarli 飲食喂養(yǎng) 12 周。評估了心臟功能、組織學和氧化應激。我們發(fā)現(xiàn)長期乙醇治療降低了心肌和 H9c2 細胞中 AdipoR2 的表達，而 AdipoRon 改善了心臟功能，降低了心肌神經酰胺水平并抑制壞死性凋亡。通過藥物干預、RNA 干擾和 AdipoR2 中的點突變，我們證明 AdipoRon 通過 PPARα 介導的脂質代謝而不是 AdipoR2 的神經酰胺酶活性降低神經酰胺水平。使用透射電子顯微鏡和活性氧 （ROS） 染色，我們發(fā)現(xiàn)慢性乙醇誘導心肌線粒體損傷和線粒體活性氧 （mtROS） 積累。同時，我們發(fā)現(xiàn) AdipoRon 通過 SIRT3-SOD2-mtROS 通路改善慢性乙醇誘導的心臟壞死性凋亡。此外，C6 神經酰胺處理概括了慢性乙醇誘導 mtROS 和壞死性凋亡的作用，而神經酰胺合成抑制劑肉豆蔻素 （MYR） 和伏馬菌素 B1 （FB1） 減弱了慢性乙醇誘導的 mtROS 和壞死性凋亡。 總的來說，AdipoRon 通過減少神經酰胺從頭合成和 mtROS 來改善慢性乙醇誘導的心臟壞死性凋亡，這突出了靶向神經酰胺代謝和氧化應激途徑在治療乙醇誘導的心臟毒性方面的治療潛力。
