Targeted Delivery and ROS-Responsive Release of Lutein Nanoassemblies Inhibit Myocardial Ischemia-Reperfusion Injury by Improving Mitochondrial Function.

IF 6.6 2区 医学 Q1 NANOSCIENCE & NANOTECHNOLOGY International Journal of Nanomedicine Pub Date : 2024-11-19 eCollection Date: 2024-01-01 DOI:10.2147/IJN.S488532
Pilong Shi, Yuetong Sha, Xinran Wang, Tao Yang, Jiawei Wu, Jiajun Zhou, Kai Liu, Xue Guan, Song Wang, Yongsheng Liu, Jingquan Gao, Hongli Sun, Tao Ban, Yonggang Cao
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Abstract

Purpose: Myocardial ischemia-reperfusion injury (MI/RI) is associated with increased oxidative damage and mitochondrial dysfunction, resulting in an elevated risk of mortality. MI/RI may be alleviated by protecting cardiomyocytes from oxidative stress. Lutein, which belongs to a class of carotenoids, has proven to be effective in cardiovascular disease treatment due to its remarkable antioxidant properties, but its application is limited due to its poor stability and low bioavailability in vivo.

Methods: In this study, a delivery system was developed based on distearoyl phosphatidyl ethanolamine (DSPE)-thiol-ketone (TK)-PEG2K (polyethylene glycol 2000) (abbreviated as DTP) and PCM-SH (CWLSEAGPVVTVRALRGTGSW) to deliver lutein (abbreviated as lutein@DTPP) to damaged myocardium. First, lutein, lutein@DTP, or lutein@DTPP were injected through the tail vein once a day for 3 days and then MI/RI model rats were established by exposing rats to ischemia for 45 min and reperfusion for 6 h. We employed a range of experimental techniques including qRT-PCR, Western blotting, transmission electron microscopy, immunohistochemistry, immunofluorescence, flow cytometry, immunoprecipitation, molecular docking, and molecular dynamics simulations.

Results: Lutein@DTPP exhibited good myocardial targeting and ROS-responsive release. Our data suggested that lutein@DTPP effectively suppresses ferroptosis in cardiomyocytes. Mechanistically, we observed an upregulation of mouse double minute-2 (MDM2) in the hearts of MI/RI models and cardiomyocytes exposed to hypoxia/reoxygenation (H/R) conditions. In addition, NADH-ubiquinone oxidoreductase 75 kDa Fe-S protein 1 (NDUFS1) translocation from the cytosol to the mitochondria was inhibited by MDM2 upregulation. Notably, no significant variation in the total NDUFS1 expression was observed in H/R-exposed cardiomyocytes following treatment with siMDM2. Further study indicated that lutein facilitates the translocation of NDUFS1 from the cytosol to mitochondria by directly binding and sequestering MDM2, thereby improving mitochondrial function and inhibiting ferroptosis.

Conclusion: Lutein@DTPP promoted the mitochondrial translocation of NDUFS1 to restore mitochondrial function and inhibited the ferroptosis of cardiomyocytes by directly binding and sequestering MDM2.

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叶黄素纳米集合体的靶向输送和 ROS 反应性释放可通过改善线粒体功能抑制心肌缺血再灌注损伤。
目的:心肌缺血再灌注损伤(MI/RI)与氧化损伤加重和线粒体功能障碍有关,导致死亡风险升高。保护心肌细胞免受氧化应激可减轻缺血再灌注损伤。叶黄素属于类胡萝卜素的一种,由于其显著的抗氧化特性,已被证明可有效治疗心血管疾病,但由于其稳定性差、体内生物利用率低,其应用受到限制:本研究开发了一种基于二硬脂酰磷脂酰乙醇胺(DSPE)-硫醇酮(TK)-PEG2K(聚乙二醇 2000)(缩写为 DTP)和 PCM-SH (CWLSEAGPVVTVRALRGTGSW)的递送系统,用于向受损心肌递送叶黄素(缩写为叶黄素@DTPP)。我们采用了一系列实验技术,包括 qRT-PCR、Western 印迹、透射电子显微镜、免疫组织化学、免疫荧光、流式细胞术、免疫沉淀、分子对接和分子动力学模拟:结果:叶黄素@DTPP具有良好的心肌靶向性和ROS反应性释放。我们的数据表明,叶黄素@DTPP 能有效抑制心肌细胞中的铁突变。从机理上讲,我们观察到在 MI/RI 模型的心脏和暴露于缺氧/复氧(H/R)条件下的心肌细胞中,小鼠双分-2(MDM2)上调。此外,MDM2 的上调抑制了 NADH-ubiquinone 氧化还原酶 75 kDa Fe-S 蛋白 1(NDUFS1)从细胞质向线粒体的转运。值得注意的是,用 siMDM2 处理 H/R 暴露的心肌细胞后,NDUFS1 的总表达量没有明显变化。进一步的研究表明,叶黄素通过直接结合和封存MDM2,促进了NDUFS1从细胞质到线粒体的转运,从而改善了线粒体功能并抑制了铁变态反应:结论:叶黄素@DTPP通过直接结合和封存MDM2,促进NDUFS1线粒体转位,恢复线粒体功能,抑制心肌细胞铁沉着。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
International Journal of Nanomedicine
International Journal of Nanomedicine NANOSCIENCE & NANOTECHNOLOGY-PHARMACOLOGY & PHARMACY
CiteScore
14.40
自引率
3.80%
发文量
511
审稿时长
1.4 months
期刊介绍: The International Journal of Nanomedicine is a globally recognized journal that focuses on the applications of nanotechnology in the biomedical field. It is a peer-reviewed and open-access publication that covers diverse aspects of this rapidly evolving research area. With its strong emphasis on the clinical potential of nanoparticles in disease diagnostics, prevention, and treatment, the journal aims to showcase cutting-edge research and development in the field. Starting from now, the International Journal of Nanomedicine will not accept meta-analyses for publication.
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