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

Autophagy Pub Date : 2025-02-01 Epub 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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Abstract

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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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。
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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