Human umbilical vein endothelial cells-derived exosomes enhance cardiac function after acute myocardial infarction by activating the PI3K/AKT signaling pathway

Currently, acute myocardial infarction (AMI) is one of the leading causes of human health issues worldwide. The sudden and continuous occlusion of the coronary artery results in myocardial hypoxic-ischemic necrosis, which is accompanied by inflammatory infiltration and fibrosis, leading to pathological cardiac remodeling. Exosome-based therapy is a promising cell-free approach for repairing the ischemic myocardium. This study aimed to explore the effects and mechanism of human umbilical vein endothelial cells (HUVECs)-derived exosomes on AMI. The results indicated that the localized injection of HUVECs-derived exosomes in the infarcted area could significantly improve cardiac function in AMI mouse models. It could also ameliorate myocardial fibrosis and decrease infarct size after AMI. Additionally, HUVECs-derived exosomes had cardioprotective effects on the H9C2 cells in hypoxic culture conditions, including increased cell viability and decreased lactate dehydrogenase (LDH) release. In both the <i>in-vivo</i> and <i>in-vitro</i> experiments, HUVECs-derived exosomes could effectively inhibit cardiomyocyte apoptosis. The low expression levels of Bcl-2–associated X protein (Bax) and cleaved caspase-3, high expression levels of B-cell lymphoma 2 (Bcl-2), phosphorylated phosphatidylinositol 3-kinase (p-PI3K), and phosphorylated protein kinase B (p-AKT) were detected in AMI mouse models treated with HUVECs-derived exosomes <i>in-vivo</i>. In conclusion, HUVECs-derived exosomes effectively enhanced cardiac function after AMI and inhibited cardiomyocyte apoptosis, which might be regulated through the phosphatidylinositol 3-kinase (PI3K)/ protein kinase B (AKT) signaling pathway.

目前，急性心肌梗死（acute myocardial infarction, AMI）是全球范围内威胁人类健康的主要病因之一。冠状动脉突发持续性闭塞会引发心肌缺血缺氧性坏死，伴随炎性浸润与纤维化进程，进而导致病理性心肌重构。基于外泌体（exosome）的治疗是修复缺血心肌的极具潜力的无细胞疗法。本研究旨在探讨人脐静脉内皮细胞（human umbilical vein endothelial cells, HUVECs）衍生外泌体对急性心肌梗死的作用及其机制。研究结果显示，在急性心肌梗死小鼠模型的梗死区域局部注射HUVECs衍生外泌体，可显著改善模型的心功能；同时能够减轻心肌纤维化程度，缩小梗死面积。此外，在缺氧培养条件下，HUVECs衍生外泌体对H9C2细胞具有心肌保护作用，可提升细胞活力并减少乳酸脱氢酶（lactate dehydrogenase, LDH）的释放。无论是体内（in-vivo）还是体外（in-vitro）实验中，HUVECs衍生外泌体均可有效抑制心肌细胞凋亡。在经HUVECs衍生外泌体体内处理的急性心肌梗死小鼠模型中，检测到Bcl-2相关X蛋白（Bcl-2–associated X protein, Bax）与裂解型半胱氨酸天冬氨酸蛋白酶-3（cleaved caspase-3）的低表达，以及B细胞淋巴瘤-2（B-cell lymphoma 2, Bcl-2）、磷酸化磷脂酰肌醇3-激酶（phosphorylated phosphatidylinositol 3-kinase, p-PI3K）与磷酸化蛋白激酶B（phosphorylated protein kinase B, p-AKT）的高表达。综上，HUVECs衍生外泌体可有效改善急性心肌梗死后的心功能，并抑制心肌细胞凋亡，其作用机制可能通过调控磷脂酰肌醇3-激酶/蛋白激酶B（phosphatidylinositol 3-kinase, PI3K/ protein kinase B, AKT）信号通路实现。