Background:Patients with acute myocardial infarction suffer systemic metabolic dysfunction via incompletely understood mechanisms. Adipocytes play critical role in metabolic homeostasis. The impact of acute myocardial infarction upon adipocyte function is unclear. Small extracellular vesicles (sEVs) critically contribute to organ-organ communication. Whether and how small extracellular vesicle mediate post-MI cardiomyocyte/adipocyte communication remain unknown.Methods:Plasma sEVs were isolated from sham control (Pla-sEV^Sham) or 3 hours after myocardial ischemia/reperfusion (Pla-sEV^MI/R) and incubated with adipocytes for 24 hours. Compared with Pla-sEV^Sham, Pla-sEV^MI/R significantly altered expression of genes known to be important in adipocyte function, including a well-known metabolic regulatory/cardioprotective adipokine, APN (adiponectin). Pla-sEV^MI/R activated 2 (PERK-CHOP and ATF6 [transcription factor 6]-EDEM [ER degradation enhancing alpha-mannosidase like protein 1] pathways) of the 3 endoplasmic reticulum (ER) stress pathways in adipocytes. These pathological alterations were also observed in adipocytes treated with sEVs isolated from adult cardiomyocytes subjected to in vivo myocardial ischemia/reperfusion (MI/R) (Myo-sEV^MI/R). Bioinformatic/RT-qPCR analysis demonstrates that the members of miR-23-27-24 cluster are significantly increased in Pla-sEV^MI/R, Myo-sEV^MI/R, and adipose tissue of MI/R animals. Administration of cardiomyocyte-specific miR-23-27-24 sponges abolished adipocyte miR-23-27-24 elevation in MI/R animals, supporting the cardiomyocyte origin of adipocyte miR-23-27-24 cluster. In similar fashion to Myo-sEV^MI/R, a miR-27a mimic activated PERK-CHOP and ATF6-EDEM-mediated ER stress. Conversely, a miR-27a inhibitor significantly attenuated Myo-sEV^MI/R-induced ER stress and restored APN production.Results:An unbiased approach identified EDEM3 (ER degradation enhancing alpha-mannosidase like protein 3) as a novel downstream target of miR-27a. Adipocyte EDEM3 deficiency phenocopied multiple pathological alterations caused by Myo-sEV^MI/R, whereas EDEM3 overexpression attenuated Myo-sEV^MI/R-resulted ER stress. Finally, administration of GW4869 or cardiomyocyte-specific miR-23-27-24 cluster sponges attenuated adipocyte ER stress, improved adipocyte endocrine function, and restored plasma APN levels in MI/R animals.Conclusions:We demonstrate for the first time that MI/R causes significant adipocyte ER stress and endocrine dysfunction by releasing miR-23-27-24 cluster-enriched small extracellular vesicle. Targeting small extracellular vesicle–mediated cardiomyocyte-adipocyte pathological communication may be of therapeutic potential to prevent metabolic dysfunction after MI/R.

中文翻译：

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缺血性心脏来源的小细胞外囊泡损害脂肪细胞功能

背景：急性心肌梗死患者通过不完全了解的机制遭受全身代谢功能障碍。脂肪细胞在代谢稳态中发挥着关键作用。急性心肌梗死对脂肪细胞功能的影响尚不清楚。小细胞外囊泡 (sEV) 对器官间通讯至关重要。小细胞外囊泡是否以及如何介导 MI 后心肌细胞/脂肪细胞通讯仍不清楚。方法：从假手术对照 (Pla-sEV ^Sham ) 或心肌缺血/再灌注后 3 小时 (Pla-sEV ^MI/R ) 中分离血浆 sEV 并孵育与脂肪细胞一起作用24小时。与 Pla-sEV ^Sham相比，Pla-sEV ^MI/R显着改变了已知对脂肪细胞功能重要的基因的表达，包括众所周知的代谢调节/心脏保护脂肪因子 APN（脂联素）。Pla-sEV ^MI/R激活脂肪细胞中 3 条内质网 (ER) 应激途径中的 2 条（PERK-CHOP 和 ATF6 [转录因子 6]-EDEM [ER 降解增强 α-甘露糖苷酶样蛋白 1] 途径）。在用从经历体内心肌缺血/再灌注（MI/R）的成年心肌细胞分离的sEV（Myo-sEV MI/ ^R）处理的脂肪细胞中也观察到这些病理改变。生物信息学/RT-qPCR分析表明，miR-23-27-24簇的成员在Pla-sEV MI ^/R、Myo-sEV ^MI/R和MI/R动物的脂肪组织中显着增加。施用心肌细胞特异性 miR-23-27-24 海绵消除了 MI/R 动物中脂肪细胞 miR-23-27-24 的升高，支持脂肪细胞 miR-23-27-24 簇的心肌细胞起源。^{与 Myo-sEV MI/R}类似，miR-27a 模拟物激活 PERK-CHOP 和 ATF6-EDEM 介导的 ER 应激。相反，miR-27a 抑制剂显着减弱 Myo-sEV ^MI/R诱导的 ER 应激并恢复 APN 的产生。结果：一种公正的方法将 EDEM3（ER 降解增强 α-甘露糖苷酶样蛋白 3）确定为 miR-27a 的新下游靶标27a. ^{脂肪细胞 EDEM3 缺乏表现出由 Myo-sEV MI/R}引起的多种病理改变，而 EDEM3 过表达减弱了 Myo-sEV ^MI/R-导致 ER 应激。最后，给予 GW4869 或心肌细胞特异性 miR-23-27-24 簇海绵可减轻 MI/R 动物的脂肪细胞 ER 应激，改善脂肪细胞内分泌功能，并恢复血浆 APN 水平。结论：我们首次证明 MI/ R 通过释放富含 miR-23-27-24 簇的小细胞外囊泡，引起显着的脂肪细胞 ER 应激和内分泌功能障碍。针对小细胞外囊泡介导的心肌细胞-脂肪细胞病理通讯可能具有预防 MI/R 后代谢功能障碍的治疗潜力。