Department of Cardiology, Jiangxi Pingxiang People's Hospital, Pingxiang 337000, P. R. China.
Department of Hematology, Jiangxi Pingxiang People's Hospital, Pingxiang 337000, P. R. China.
ACS Biomater Sci Eng. 2022 Apr 11;8(4):1696-1705. doi: 10.1021/acsbiomaterials.1c01198. Epub 2022 Mar 7.
Although microRNA-153-3p (miR-153-3p) has been demonstrated to confer protective roles in ischemia/reperfusion injury, its potential role in myocardial infarction (MI) remains undefined. Small-molecule modifiers and nanoparticles loaded with microRNAs (miRNAs) have emerged as potential therapeutic reagents for MI treatment. In this study, we prepared liposome nanoparticles, hyaluronic acid (HA)-cationic liposomes (CLPs) complex, for the delivery of miR-153-3p and delineated the mechanistic actions of miR-153-3p modified by nHA-CLPs in MI-induced injury. Our data suggested that nHA-CLPs-loaded miR-153-3p protected cardiomyocytes against MI-induced cardiomyocyte apoptosis and myocardial injury. miR-153-3p was bioinformatically predicted and experimentally verified to bind to Krüppel-like factor 5 (KLF5) 3'UTR and negatively regulate its expression. Hypoxia was adopted to stimulate MI-induced injury to cardiomyocytes in vitro, in which miR-153-3p presented anti-apoptotic potential. However, restoration of KLF5 reversed this anti-apoptotic effect of miR-153-3p. Furthermore, KLF5 was demonstrated to be an activator of the NF-κB pathway. KLF5 enhanced cardiomyocyte apoptosis and inflammation under hypoxic conditions through NF-κB pathway activation, while nHA-CLPs-loaded miR-153-3p suppressed inflammation by blocking the NF-κB pathway. Collectively, our findings suggested the cardioprotective role of miR-153-3p against MI and the successful delivery of miR-153-3p by nHA-CLPs. The identification of KLF5-mediated activation of NF-κB pathway as an apoptotic and inflammatory mechanism aids in better understanding of the biology of MI and development of novel therapeutic strategies for MI.
虽然 microRNA-153-3p（miR-153-3p）已被证明在缺血/再灌注损伤中具有保护作用，但它在心肌梗死（MI）中的潜在作用仍未确定。携带 microRNAs（miRNAs）的小分子调节剂和纳米颗粒已成为 MI 治疗的潜在治疗试剂。在这项研究中，我们制备了脂质体纳米颗粒，即透明质酸（HA）-阳离子脂质体（CLP）复合物，用于递送 miR-153-3p，并阐明了 nHA-CLP 修饰的 miR-153-3p 在 MI 诱导损伤中的作用机制。我们的数据表明，nHA-CLP 负载的 miR-153-3p 可保护心肌细胞免受 MI 诱导的心肌细胞凋亡和心肌损伤。miR-153-3p 通过生物信息学预测和实验验证与 Krüppel 样因子 5（KLF5）3'UTR 结合并负调控其表达。采用缺氧刺激体外 MI 诱导的心肌细胞损伤，miR-153-3p 表现出抗凋亡潜能。然而，KLF5 的恢复逆转了 miR-153-3p 的这种抗凋亡作用。此外，KLF5 被证明是 NF-κB 通路的激活剂。KLF5 通过激活 NF-κB 通路增强缺氧条件下的心肌细胞凋亡和炎症，而 nHA-CLP 负载的 miR-153-3p 通过阻断 NF-κB 通路抑制炎症。总之，我们的研究结果表明 miR-153-3p 在 MI 中的心脏保护作用以及 nHA-CLP 对 miR-153-3p 的成功递送。鉴定 KLF5 介导的 NF-κB 通路激活作为一种凋亡和炎症机制有助于更好地理解 MI 的生物学特性，并为 MI 的新型治疗策略的发展提供了新的思路。
