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

IF 5.2 2区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Life sciences Pub 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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引用次数: 0

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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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.