Mir221-和Mir222-富集的adsc-外泌体通过调节BNIP3-MAP1LC3B-BBC3/PUMA通路减轻暴露于PM-加重的心脏缺血再灌注损伤。

Autophagy Pub Date : 2024-09-08 DOI:10.1080/15548627.2024.2395799

Tzu-Lin Lee, Wen-Chi Shen, Ya-Chun Chen, Tsai-Chun Lai, Shu-Rung Lin, Shu-Wha Lin, I-Shing Yu, Yen-Hsiu Yeh, Tsai-Kun Li, I-Ta Lee, Chiang-Wen Lee, Yuh-Lien Chen

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引用次数: 0

摘要

流行病学显示，细颗粒物（PM）暴露与心血管疾病之间存在密切关系。然而，可吸入颗粒物是否会加重心肌缺血再灌注（I/R）损伤仍是未知数，相关机制也不清楚。我们之前的研究表明，脂肪干细胞衍生的外泌体（ADSC-Exos）含有高水平的Mir221和Mir222。本研究探讨了暴露于PM通过有丝分裂和细胞凋亡对I/R诱导的心脏损伤的影响，以及Mir221和Mir222在ADSC-Exos中的潜在作用。给野生型、mir221-和mir222-基因敲除（KO）以及Mir221-和Mir222-基因缺失转基因（TG）小鼠气管内注射 PM（10 mg/kg）。24 小时后，小鼠左冠状动脉结扎 30 分钟，然后再灌注（I/R）3 小时。H9c2 心肌细胞在 1%O2 条件下培养 6 小时，然后再氧合 12 小时（缺氧-再氧合 [H/R]）。PM 通过增加 ROS 水平和导致线粒体功能障碍加重了 I/R（或 H/R）心脏损伤，从而增加了线粒体裂变相关蛋白（DNM1L/Drp1 和 MFF）和有丝分裂相关蛋白（BNIP3 和 MAP1LC3B/LC3B）在体内和体外的表达。用ADSC-Exos或Mir221-和Mir222-模拟物治疗可显著减轻PM+I/R诱导的心脏损伤。重要的是，ADSC-Exos含有Mir221和Mir222，可直接靶向BNIP3、MAP1LC3B/LC3B和BBC3/PUMA，降低它们的表达，最终减少心肌细胞的有丝分裂和凋亡。本研究数据显示，ADSC-Exos治疗通过Mir221和Mir222-BNIP3-MAP1LC3B-BBC3/PUMA通路调控有丝分裂和细胞凋亡，显著减轻PM+I/R造成的心脏损伤。本研究揭示了 ADSC-Exos 在缓解 PM 引起的心肌 I/R 损伤加重方面的新的治疗潜力：缩写：ADSC-Exos：脂肪源性干细胞外泌体；AL：自溶体；ATP：三磷酸腺苷；BBC3/PUMA：BCL2结合成分3；BNIP3：BCL2/腺病毒E1B相互作用蛋白3；CASP3：caspase 3；CASP9：caspase 9；CDKN1B/p27：细胞周期蛋白依赖性激酶抑制剂1B；CVD：心血管疾病；DCFF-Exos：脂肪源性干细胞外泌体：DCFH-DA：2',7'-dichlorodihydrofluorescein diacetate；DHE：dihydroethidium；DNM1L/Drp1：dynamin 1-like；EF：ejection fraction；FS：fractional shortening；H/R：hypoxia-reoxygenation；I/R：ischemia-reperfusion；LDH：lactate dehydrogenase；MAP1LC3B/LC3B：MFF：线粒体裂解因子；miRNA：微RNA；NAC：N-乙酰半胱氨酸；OCR：耗氧量；PIK3C3/Vps34：磷脂酰肌醇 3-激酶催化亚基 3 型；PM：微粒物质；PRKAA1/AMPK：ROS：活性氧；SQSTM1/p62：序列体 1；TEM：透射电子显微镜；TRP53/p53：转化相关蛋白 53；TUNEL：末端脱氧核苷酸转移酶 dUTP 缺口标记。

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Mir221- and Mir222-enriched adsc-exosomes mitigate PM exposure-exacerbated cardiac ischemia-reperfusion injury through the modulation of the BNIP3-MAP1LC3B-BBC3/PUMA pathway.

Epidemiology has shown a strong relationship between fine particulate matter (PM) exposure and cardiovascular disease. However, it remains unknown whether PM aggravates myocardial ischemia-reperfusion (I/R) injury, and the related mechanisms are unclear. Our previous study has shown that adipose stem cell-derived exosomes (ADSC-Exos) contain high levels of Mir221 and Mir222. The present study investigated the effects of PM exposure on I/R-induced cardiac injury through mitophagy and apoptosis, as well as the potential role of Mir221 and Mir222 in ADSC-Exos. Wild-type, mir221- and mir222-knockout (KO), and Mir221- and Mir222-overexpressing transgenic (TG) mice were intratracheally injected with PM (10 mg/kg). After 24 h, mice underwent left coronary artery ligation for 30 min, followed by 3 h of reperfusion (I/R). H9c2 cardiomyocytes were cultured under 1% O₂ for 6 h, then reoxygenated for 12 h (hypoxia-reoxygenation [H/R]). PM aggravated I/R (or H/R) cardiac injury by increasing ROS levels and causing mitochondrial dysfunction, which increased the expression of mitochondrial fission-related proteins (DNM1L/Drp1 and MFF) and mitophagy-related proteins (BNIP3 and MAP1LC3B/LC3B) in vivo and in vitro. Treatment with ADSC-Exos or Mir221- and Mir222-mimics significantly reduced PM+I/R-induced cardiac injury. Importantly, ADSC-Exos contain Mir221 and Mir222, which directly targets BNIP3, MAP1LC3B/LC3B, and BBC3/PUMA, decreasing their expression and ultimately reducing cardiomyocyte mitophagy and apoptosis. The present data showed that ADSC-Exos treatment regulated mitophagy and apoptosis through the Mir221 and Mir222-BNIP3-MAP1LC3B-BBC3/PUMA pathway and significantly reduced the cardiac damage caused by PM+I/R. The present study revealed the novel therapeutic potential of ADSC-Exos in alleviating PM-induced exacerbation of myocardial I/R injury.Abbreviation: ADSC-Exos: adipose-derived stem cell exosomes; AL: autolysosome; ATP: adenosine triphosphate; BBC3/PUMA: BCL2 binding component 3; BNIP3: BCL2/adenovirus E1B interacting protein 3; CASP3: caspase 3; CASP9: caspase 9; CDKN1B/p27: cyclin dependent kinase inhibitor 1B; CVD: cardiovascular disease; DCFH-DA: 2',7'-dichlorodihydrofluorescein diacetate; DHE: dihydroethidium; DNM1L/Drp1: dynamin 1-like; EF: ejection fraction; FS: fractional shortening; H/R: hypoxia-reoxygenation; I/R: ischemia-reperfusion; LDH: lactate dehydrogenase; MAP1LC3B/LC3B: microtubule-associated protein 1 light chain 3 beta; MFF: mitochondrial fission factor; miRNA: microRNA; NAC: N-acetylcysteine; OCR: oxygen consumption rate; PIK3C3/Vps34: phosphatidylinositol 3-kinase catalytic subunit type 3; PM: particulate matter; PRKAA1/AMPK: protein kinase AMP-activated catalytic subunit alpha 1; ROS: reactive oxygen species; SQSTM1/p62: sequestosome 1; TEM: transmission electron microscopy; TRP53/p53: transformation related protein 53; TUNEL: terminal deoxynucleotidyl transferase dUTP nick end labeling.

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Autophagy

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