Heart Center of Henan Provincial People's Hospital, Central China Fuwai Hospital Central China Fuwai Hospital of Zhengzhou University Zhengzhou Henan China.
Department of Cardiology The First Affiliated Hospital of Xi'an Jiao Tong University Xi'an Shaanxi China.
J Am Heart Assoc. 2023 Aug;12(15):e029415. doi: 10.1161/JAHA.123.029415. Epub 2023 Jul 25.
Background The epicardial adipose tissue (EAT) of metabolic syndrome (MetS) is abnormally accumulated with dysfunctional secretion of adipokines, closely relating to cardiac dysfunction. The current study was designed to identify the effects of EAT-derived leptin on the myocardium of MetS rats and explore the potential molecular mechanisms. Methods and Results A MetS rat model was established in 8-week-old Wistar rats by a 12-week high-fat diet. MetS rats exhibited increased leptin secretion from EAT, cardiac hypertrophy, and diastolic dysfunction with preserved systolic function. The myocardium of MetS rats had abnormal structure, increased oxidative stress injury, and higher inflammatory factor levels, especially the subepicardial myocardium, which was correlated with the EAT-derived leptin level but not the serum leptin. The EAT was separated from each group of rats to prepare EAT-conditioned medium. H9C2 rat cardiomyoblasts were treated with EAT-conditioned medium or leptin, plus various inhibitors. EAT-derived leptin from MetS rats promoted mitochondrial oxidative stress and dysfunction, induced mitochondrial pathway apoptosis, and inhibited cell viability in H9C2 cardiomyoblasts via the protein kinase C/reduced nicotinamide adenine dinucleotide phosphate oxidase/reactive oxygen species (PKC/NADPH oxidase/ROS) pathway. EAT-derived leptin from MetS rats stimulated inflammation in H9C2 cardiomyocytes by promoting activator protein 1 nuclear translocation via the PKC/NADPH oxidase/ROS pathway. Leptin promoted the interaction between p-p47 and gp91 in H9C2 cardiomyocytes via protein kinase C, activating nicotinamide adenine dinucleotide phosphate oxidase, increasing reactive oxygen species generation, and inhibiting cell viability. Conclusions EAT-derived leptin induces MetS-related myocardial injury through the following 2 cooperative ways via PKC/NADPH oxidase/ROS pathway: (1) inducing mitochondrial pathway apoptosis by promoting mitochondrial oxidative stress and dysfunction; and (2) stimulating inflammation by promoting activator protein 1 nuclear translocation.
代谢综合征（MetS）的心外膜脂肪组织（EAT）异常积聚，脂肪细胞因子分泌功能障碍，与心脏功能障碍密切相关。本研究旨在确定 EAT 衍生的瘦素对 MetS 大鼠心肌的影响，并探讨潜在的分子机制。
通过 12 周高脂肪饮食，在 8 周龄 Wistar 大鼠中建立 MetS 大鼠模型。MetS 大鼠表现出 EAT 分泌的瘦素增加、心肌肥大和舒张功能障碍，而收缩功能保持不变。MetS 大鼠的心肌结构异常，氧化应激损伤增加，炎症因子水平升高，特别是心外膜下心肌，与 EAT 衍生的瘦素水平相关，但与血清瘦素无关。从各组大鼠中分离出 EAT 以制备 EAT 条件培养基。用 EAT 条件培养基或瘦素加各种抑制剂处理 H9C2 大鼠心肌细胞。MetS 大鼠来源的 EAT 衍生瘦素通过蛋白激酶 C/还原型烟酰胺腺嘌呤二核苷酸磷酸氧化酶/活性氧（PKC/NADPH 氧化酶/ROS）途径促进线粒体氧化应激和功能障碍，诱导线粒体途径凋亡，并抑制 H9C2 心肌细胞的细胞活力。MetS 大鼠来源的 EAT 衍生瘦素通过 PKC/NADPH 氧化酶/ROS 途径促进激活蛋白 1 核易位，刺激 H9C2 心肌细胞炎症。瘦素通过蛋白激酶 C 促进 p-p47 与 gp91 在 H9C2 心肌细胞中的相互作用，激活烟酰胺腺嘌呤二核苷酸磷酸氧化酶，增加活性氧的产生，抑制细胞活力。
EAT 衍生的瘦素通过 PKC/NADPH 氧化酶/ROS 途径通过以下 2 种协同方式诱导 MetS 相关心肌损伤：（1）通过促进线粒体氧化应激和功能障碍诱导线粒体途径凋亡；（2）通过促进激活蛋白 1 核易位刺激炎症。
