Exosomes from Hypoxic Pretreatment ADSCs Ameliorate Cardiac Damage Post-MI via Activated circ-Stt3b/miR-15a-5p/GPX4 Signaling and Decreased Ferroptosis.

IF 3.4 3区 医学 Q2 CARDIAC & CARDIOVASCULAR SYSTEMS Cardiovascular Toxicology Pub Date : 2024-11-01 Epub Date: 2024-08-27 DOI:10.1007/s12012-024-09915-9
Jili Liu, Zhaolin Wang, Anhua Lin, Na Zhang
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Abstract

Accumulation studies confirmed that oxidative stress caused by ischemia after myocardial infarction (MI) is an important cause of ventricular remodeling. Exosome secretion through hypoxic pretreatment adipose-derived mesenchymal stem cells (ADSCs) ameliorates myocardial damaging post-MI. However, if ADSCs exosome can improve the microenvironment and ameliorate cardiac damage post-MI still unknown. Next-generation sequencing (NGS) was used to study abnormally expressed circRNAs in hypoxic pretreatment ADSC exosomes (HExos) and untreated ADSC exosomes (Exos). Bioinformatics and luciferase reporting were used to elucidate interaction correlation related to circRNA, mRNA, and miRNA. HL-1 cells were used to analyze the reactive oxygen species (ROS) and apoptosis under hypoxic conditions using immunofluorescence and flow cytometry. An MI mouse model was constructed and the therapeutic effect of Exos was determined using immunohistochemistry, immunofluorescence, and ELISA. The results showed that HExos had a more pronounced treatment effect than ADSC Exos on cardiac damage amelioration after MI. NGS showed that circ-Stt3b plays a role in HExo-mediated cardiac damage repair after MI. Overexpression of circ-Stt3b decreased apoptosis, ROS level, and inflammatory factor expression in HL-1 cells under hypoxic conditions. Bioinformatics and luciferase reporting data validated miR-15a-5p and GPX4 as downstream circ-Stt3b targets. GPX4 downregulation or miR-15a-5p overexpression reversed protective effect regarding circ-Stt3b upon HL-1 cells after exposure to a hypoxic microenvironment. Overexpression of circ-Stt3b increased the treatment effect of ASDSC Exos on cardiac damage amelioration after MI. Taken together, the study results demonstrated that Exos from hypoxic pretreatment ADSCs ameliorate cardiac damage post-MI through circ-Stt3b/miR-15a-5p/GPX4 signaling activation and decreased ferroptosis.

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低氧预处理 ADSCs 的外泌体通过激活 circ-Stt3b/miR-15a-5p/GPX4 信号传导和减少铁凋亡改善心肌梗死后的心脏损伤
大量研究证实,心肌梗塞(MI)后缺血引起的氧化应激是心室重塑的重要原因。通过缺氧预处理脂肪间充质干细胞(ADSCs)分泌的外泌体可改善心肌梗死后的心肌损伤。然而,ADSCs外泌体能否改善微环境并减轻心肌梗死后的心脏损伤仍是未知数。研究人员利用新一代测序技术(NGS)研究了缺氧预处理 ADSC 外泌体(HExos)和未处理 ADSC 外泌体(Exos)中异常表达的 circRNAs。生物信息学和荧光素酶报告用于阐明circRNA、mRNA和miRNA的相互作用相关性。利用免疫荧光和流式细胞术分析了HL-1细胞在缺氧条件下的活性氧(ROS)和细胞凋亡。建立了心肌梗死小鼠模型,并使用免疫组化、免疫荧光和酶联免疫吸附测定了 Exos 的治疗效果。结果表明,与 ADSC Exos 相比,HExos 对改善心肌梗死后的心脏损伤有更明显的治疗效果。NGS显示,circ-Stt3b在HExo介导的心肌梗死后心脏损伤修复中发挥作用。过表达 circ-Stt3b 能降低缺氧条件下 HL-1 细胞的凋亡、ROS 水平和炎症因子的表达。生物信息学和荧光素酶报告数据验证了 miR-15a-5p 和 GPX4 是 circ-Stt3b 的下游靶点。GPX4 下调或 miR-15a-5p 过表达可逆转 circ-Stt3b 对暴露于缺氧微环境中的 HL-1 细胞的保护作用。过表达 circ-Stt3b 增加了 ASDSC Exos 对改善心肌梗死后心脏损伤的治疗效果。综上所述,研究结果表明,缺氧预处理的ADSCs Exos可通过circ-Stt3b/miR-15a-5p/GPX4信号激活和减少铁变态反应来改善心肌梗死后的心脏损伤。
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来源期刊
Cardiovascular Toxicology
Cardiovascular Toxicology 医学-毒理学
CiteScore
6.60
自引率
3.10%
发文量
61
审稿时长
>12 weeks
期刊介绍: Cardiovascular Toxicology is the only journal dedicated to publishing contemporary issues, timely reviews, and experimental and clinical data on toxicological aspects of cardiovascular disease. CT publishes papers that will elucidate the effects, molecular mechanisms, and signaling pathways of environmental toxicants on the cardiovascular system. Also covered are the detrimental effects of new cardiovascular drugs, and cardiovascular effects of non-cardiovascular drugs, anti-cancer chemotherapy, and gene therapy. In addition, Cardiovascular Toxicology reports safety and toxicological data on new cardiovascular and non-cardiovascular drugs.
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