Department of Cardiology, The 2nd Affiliated Hospital of Harbin Medical University, 148 Health Care Road, Harbin, Heilongjiang, China.
The Key Laboratory of Myocardial Ischemia, Chinese Ministry of Education, Harbin, 150000, Heilongjiang, China.
J Nanobiotechnology. 2023 Oct 4;21(1):362. doi: 10.1186/s12951-023-02076-x.
Endothelial cell dysfunction is a major cause of early atherosclerosis. Although the role of extracellular vesicles in stabilizing atherosclerotic plaques is well established, the effect of circulating exosomes on plaque formation is still unknown. Here, we explored the effect of exosomes on atherosclerosis based on the function that exosomes can act on intercellular communication.
We extracted serum exosomes from the blood of CHD patients (CHD-Exo) and healthy individuals (Con-Exo). The obtained exosomes were co-cultured with human umbilical vein endothelial cells (HUVECs) in vitro. In addition, we determined that circ_0001785 functions as a competing endogenous RNA (ceRNAs) in coronary artery disease by dual luciferase reporter gene analysis. The protective effect of circ_0001785 against endothelial cell injury was also verified using over-expression lentiviral transfection functional assays. In vivo experiments, we injected over-expressed circ_0001785 lentivirus into the tail vein of mice to observe its therapeutic effect on a mouse model of atherosclerosis.
The vitro co-cultured results showed that the amount of plasma-derived exosomes have an increase in patients with coronary artery disease, and the inflammation and apoptosis of endothelial cells were exacerbated. Over-expression of circ_0001785 reduced endothelial cell injury through the ceRNA network pathway of miR-513a-5p/TGFBR3. Quantitative reverse transcription-polymerase chain reaction identified that the expressed amount of circ_0001785 was reduced in the circulating peripheral blood of CHD patients and increased within human and mouse atherosclerotic plaque tissue. The results of in vivo experiments showed that circ_0001785 reduced aortic endothelial cell injury and the formation of intraplaque neo-vascularization, and enhanced left ventricular diastolic function, thereby delaying the development of atherosclerosis in mice.
Our results demonstrated a new biomarker, exosome-derived circ_0001785, for atherogenesis, which can reduce endothelial cell injury and thus delay atherogenesis through the miR-513a-5p/TGFBR3 ceRNA network mechanism, providing an exosome-based intervention strategy for atherosclerosis.
内皮细胞功能障碍是动脉粥样硬化早期的主要原因。尽管细胞外囊泡在稳定动脉粥样硬化斑块中的作用已得到充分证实，但循环外泌体对斑块形成的影响仍不清楚。在这里，我们基于外泌体可以作用于细胞间通讯的功能，探讨了外泌体对动脉粥样硬化的影响。
我们从 CHD 患者（CHD-Exo）和健康个体（Con-Exo）的血液中提取血清外泌体。体外将获得的外泌体与人脐静脉内皮细胞（HUVECs）共培养。此外，我们通过双荧光素酶报告基因分析确定 circ_0001785 是冠心病的竞争性内源性 RNA（ceRNA）。还通过过表达慢病毒转染功能测定验证了 circ_0001785 对内皮细胞损伤的保护作用。在体内实验中，我们将过表达 circ_0001785 的慢病毒注入小鼠尾静脉，观察其对动脉粥样硬化小鼠模型的治疗效果。
体外共培养结果显示，冠心病患者血浆衍生外泌体数量增加，内皮细胞炎症和凋亡加剧。过表达 circ_0001785 通过 miR-513a-5p/TGFBR3 的 ceRNA 网络通路减少内皮细胞损伤。定量逆转录聚合酶链反应鉴定出 CHD 患者循环外周血中 circ_0001785 的表达量降低，而在人和小鼠动脉粥样硬化斑块组织中增加。体内实验结果表明，circ_0001785 减少了主动脉内皮细胞损伤和斑块内新生血管形成，增强了左心室舒张功能，从而延缓了小鼠动脉粥样硬化的发展。
我们的研究结果表明，外泌体衍生的 circ_0001785 是动脉粥样硬化形成的一种新的生物标志物，它可以通过 miR-513a-5p/TGFBR3 ceRNA 网络机制减少内皮细胞损伤，从而延缓动脉粥样硬化的发生，为动脉粥样硬化提供了一种基于外泌体的干预策略。
