MiR-222-3p loaded stem cell nanovesicles repair myocardial ischemia damage via inhibiting mitochondrial oxidative stress

IF 5.1 2区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Life sciences Pub Date : 2025-03-15 Epub Date: 2025-02-06 DOI:10.1016/j.lfs.2025.123447

Mei Liu , Le Wang , Zhao Liu , Dongyue Liu , Tianshuo Li , Lini Ding , Shasha Zeng , Zi Wang , Jiaqiu Wang , Fan Zhang , Jun Zhang , Limin Zhang , Meng Li , Gang Liu , Xianyun Wang , Mingqi Zheng

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Abstract

Aims

Mitochondrial oxidative stress (MOS) is a key contributor to poor cardiac function and a major driver of myocardial ischemia-reperfusion injury (MIRI). Our previous research demonstrated that stem cell-derived nanovesicles (NVs) enhanced cardiac function following ischemia-reperfusion (I/R) injury, although the underlying mechanisms remain unclear. We constructed and characterized miR-222-3p-loaded NVs.

Materials and methods

An in vitro hypoxia-reoxygenation (H/R) model was established using H9C2 cardiomyocytes. Mitochondrial oxidative respiratory function was assessed using Seahorse XF technology, while mitochondrial reactive oxygen species (mtROS) levels were quantified via flow cytometry. Additional assessments included mitochondrial permeability transition pore (mPTP) status, mitochondrial membrane potential, and mitochondrial DNA (mtDNA) integrity. An in vivo H/R model was developed using C57BL/6 mice. The therapeutic effects of NVs on MOS reduction and cardiac function improvement were evaluated through Masson's staining, immunofluorescence, echocardiography, transmission electron microscopy (TEM), and positron emission tomography/computed tomography (PET/CT).

Key findings

RNA immunoprecipitation (RIP) confirmed that miR-222-3p directly targets cyp1a1. Overexpression of miR-222-3p or knockdown of cyp1a1 significantly improved mitochondrial activity in cardiomyocytes and conferred protection against I/R injury. Conversely, overexpression of cyp1a1 abrogated the protective effects of miR-222-3p. In vivo, NV treatment enhanced cardiac function, reduced MOS, and improved mitochondrial respiratory capacity in MIRI model mice. NV treatment, via miR-222-3p-mediated suppression of cyp1a1, mitigates MOS, enhances mitochondrial respiratory function, and improves cardiac outcomes in MIRI models.

Significance

These findings provide a foundational basis for the clinical translation of NV-based therapies.

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负载MiR-222-3p的干细胞纳米囊泡通过抑制线粒体氧化应激修复心肌缺血损伤。

目的：线粒体氧化应激（MOS）是心功能不良的关键因素，也是心肌缺血再灌注损伤（MIRI）的主要驱动因素。我们之前的研究表明，干细胞衍生的纳米囊泡（NVs）可以增强缺血再灌注（I/R）损伤后的心脏功能，尽管其潜在机制尚不清楚。我们构建并表征了mir -222-3p负载的nv。材料与方法：采用H9C2心肌细胞建立体外缺氧复氧（H/R）模型。采用Seahorse XF技术评估线粒体氧化呼吸功能，通过流式细胞术定量线粒体活性氧（mtROS）水平。其他评估包括线粒体通透性、过渡孔（mPTP）状态、线粒体膜电位和线粒体DNA （mtDNA）完整性。以C57BL/6小鼠为实验对象，建立小鼠体内H/R模型。通过马松染色、免疫荧光、超声心动图、透射电子显微镜（TEM）、正电子发射断层扫描/计算机断层扫描（PET/CT）评价NVs对MOS降低和心功能改善的治疗效果。主要发现：RNA免疫沉淀（RIP）证实miR-222-3p直接靶向cyp1a1。过表达miR-222-3p或敲低cyp1a1可显著改善心肌细胞线粒体活性，并可保护心肌细胞免受I/R损伤。相反，cyp1a1的过表达消除了miR-222-3p的保护作用。在体内，NV治疗增强了MIRI模型小鼠的心功能，降低了MOS，并改善了线粒体呼吸能力。在MIRI模型中，NV治疗通过mir -222-3p介导的cyp1a1抑制，减轻了MOS，增强了线粒体呼吸功能，改善了心脏预后。意义：本研究结果为nvv治疗的临床转化提供了基础依据。

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来源期刊

Life sciences 医学-药学

CiteScore

12.20

自引率

1.60%

发文量

841

审稿时长

6 months

期刊介绍： Life Sciences is an international journal publishing articles that emphasize the molecular, cellular, and functional basis of therapy. The journal emphasizes the understanding of mechanism that is relevant to all aspects of human disease and translation to patients. All articles are rigorously reviewed. The Journal favors publication of full-length papers where modern scientific technologies are used to explain molecular, cellular and physiological mechanisms. Articles that merely report observations are rarely accepted. Recommendations from the Declaration of Helsinki or NIH guidelines for care and use of laboratory animals must be adhered to. Articles should be written at a level accessible to readers who are non-specialists in the topic of the article themselves, but who are interested in the research. The Journal welcomes reviews on topics of wide interest to investigators in the life sciences. We particularly encourage submission of brief, focused reviews containing high-quality artwork and require the use of mechanistic summary diagrams.