This study aims to investigate the biological role of DRP1 in myocardial infarction (MI) in concert with hyperlipidemia (HL). Based on the available literatures, 10 genes related to MI with HL (HL-MI) were screened and detected in clinical samples. High-fat diet (HFD) was used to establish HL rat models, after which the rats were subcutaneously injected with PBS or isoproterenol hydrochloride to induce acute MI. Then, rats with HL-MI were injected with pcDNA3.1, pcDNA3.1-DRP1, sh-NC, or sh-DRP1. Serum levels of total cholesterol (TC), triglycerides (TG), high-density lipoprotein-cholesterol (HDL-C), and low-density lipoprotein-cholesterol (LDL-C) were measured. Cardiac function was evaluated by detecting left ventricular fractional shortening (LVFS) and left ventricular ejection fraction (LVEF). Infarct size and histopathological changes were assessed as well as myocardial apoptosis and collagen deposition. The concentration of IL-6, IL-1β, and TNF-α in rat serum and cardiac tissues was also measured by ELISA. Mitochondrial function was shown by measuring the morphology, mitochondrial membrane potential (MMP), and intracellular reactive oxygen species (ROS) level. Pro-apoptotic proteins (Bax, caspase-1, and cleaved caspase-1) and NLRP3 inflammasome activation were also assessed. The expressions of the 10 genes were measured in clinical samples and DRP1 was selected for further experiments with significantly upregulated expression in MI patients. HFD-induced rats showed increased body weight, concurrent with higher levels of TG, TC, and LDL-C and lower HDL-C level. Compared with the BD-PBS group, the HFD-PBS group presented higher mRNA and protein expression levels of DRP1, exacerbated cardiac functions, enlarged infarct size, loss of cardiomyocytes, and disordered island cardiomyocytes. In the HL-MI rat model, injection of pcDNA3.1-DRP1 enhanced the levels of serum lipids and inflammation cytokines, induced loss of a number of cardiomyocytes and collagen deposition, and decreased LVFS and LVEF, while injection of sh-DRP1 ameliorated myocardial injuries, inflammation, and cardiomyocyte apoptosis and fibrosis. In coronary artery endothelial cells from the rats, loss of MMP was observed in the HFD-MI, LV-NC, LV-DRP1, and sh-NC groups and concomitantly, the sh-DRP1group showed increased MMP and decreased levels of mitochondrial ROS, cytochrome C, pro-apoptotic proteins, and NLRP3. Inhibition of DRP1 markedly suppressed HL, systematic inflammation, and myocardial injuries induced by HL-MI through partly restoring mitochondrial function and reducing NLRP3 expression.

本研究旨在探讨 DRP1 在心肌梗死 (MI) 与高脂血症 (HL) 中的生物学作用。根据现有文献，在临床样本中筛选和检测了10个与HL相关的MI（HL-MI）基因。采用高脂饮食(HFD)建立HL大鼠模型，大鼠皮下注射PBS或盐酸异丙肾上腺素诱导急性心肌梗死。然后，给患有 HL-MI 的大鼠注射 pcDNA3.1、pcDNA3.1-DRP1、sh-NC 或 sh-DRP1。测量了总胆固醇（TC）、甘油三酯（TG）、高密度脂蛋白胆固醇（HDL-C）和低密度脂蛋白胆固醇（LDL-C）的血清水平。通过检测左心室缩短分数 (LVFS) 和左心室射血分数 (LVEF) 来评估心功能。评估梗死面积和组织病理学变化以及心肌细胞凋亡和胶原沉积。还通过ELISA测量大鼠血清和心脏组织中IL-6、IL-1β和TNF-α的浓度。通过测量形态、线粒体膜电位 (MMP) 和细胞内活性氧 (ROS) 水平来显示线粒体功能。还评估了促凋亡蛋白（Bax、caspase-1 和切割的 caspase-1）和 NLRP3 炎性体活化。在临床样本中测量了 10 个基因的表达，并选择 DRP1 进行进一步的实验，在 MI 患者中表达显着上调。HFD 诱导的大鼠体重增加，同时 TG、TC 和 LDL-C 水平升高，HDL-C 水平降低。与BD-PBS组相比，HFD-PBS组表现出更高的DRP1 mRNA和蛋白表达水平、心脏功能恶化、梗死面积扩大、心肌细胞丢失和岛状心肌细胞紊乱。在 HL-MI 大鼠模型中，注射 pcDNA3.1-DRP1 提高了血脂和炎症细胞因子的水平，诱导了一些心肌细胞和胶原沉积的损失，降低了 LVFS 和 LVEF，而注射 sh-DRP1 改善了心肌损伤、炎症和心肌细胞凋亡和纤维化。在大鼠冠状动脉内皮细胞中，HFD-MI、LV-NC、LV-DRP1 和 sh-NC 组观察到 MMP 丢失，同时，sh-DRP1 组显示 MMP 增加，线粒体 ROS 水平降低，细胞色素 C、促凋亡蛋白和 NLRP3。抑制 DRP1 显着抑制 HL，