Exosomal microRNA-122 mediates obesity-related cardiomyopathy through suppressing mitochondrial ADP-ribosylation factor-like 2
Exosomal microRNA-122 mediates obesity-related cardiomyopathy through suppressing mitochondrial ADP-ribosylation factor-like 2
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外泌体 microRNA-122 通过抑制线粒体 ADP-核糖基化因子样 2 介导肥胖相关心肌病
DOI：
10.1042/cs20190558
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发表时间：
2019
期刊：
影响因子：
6
通讯作者：
Xiang Xie
中科院分区：
文献类型：
--
作者：
Wang Yongshun;Jin Pianpian;Liu Jingjin;Xiang Xie
新兴的研究表明，microRNAs（miRs）参与了包括心血管疾病在内的多种代谢并发症的发展。其中，肝脏分泌的miR-122的循环水平与临床研究中心脏疾病的几种后果密切相关，并且miR-122的过表达损害心肌细胞功能。然而，目前尚不清楚miR-122是否可以调节肥胖症的心脏生物学。因此，本研究旨在揭示miR-122在心脏代谢紊乱中的作用及其可能的分子机制。通过临床样本和高脂饮食喂养的小鼠，我们研究了miR-122在肥胖相关心肌病中的生理作用。此外，本研究探讨了外泌体miR-122刺激下小鼠原代心肌细胞线粒体功能的变化。在临床样品和肥胖小鼠中，外泌体miR-122的循环水平与心脏功能障碍参数正相关，包括射血分数（EF）降低和NT-proBNP水平升高。人血浆外泌体将miR-122转运到小鼠原代心肌细胞中，并损害线粒体ATP产生和氧消耗，而miR-122海绵改善了这些抑制作用。在饮食诱导的小鼠中，增加的肝脏和循环外泌体miR-122使心脏结构和功能指数恶化，并抑制线粒体功能。肝脏特异性阻断miR-122可减弱异常心脏重塑。在机制上，miR-122在体外和体内直接结合并抑制线粒体蛋白ADP-核糖基化因子样2（Arl-2）。Arl-2的敲低消除了miR-122海绵在外泌体处理的小鼠原代心肌细胞中的线粒体益处。总之，我们的研究首次表明，肝脏分泌的exosomal.miR-122在代谢性心肌病的发生发展中起着关键作用，miR-122/线粒体Arl-2信号通路影响心脏能量稳态。
Emerging studies have demonstrated that microRNAs (miRs) participate in the development.of multiple metabolic complications including cardiovascular diseases. Among them, circulating level of liver-secreted miR-122 was closely correlated with several consequence of.heart diseases in clinical studies, and overexpression of miR-122 impaired cardiomyocyte.function. However, it was unknown whether miR-122 could regulate cardiac biology in obesity. Therefore, present study was to disclose the role of miR-122 in cardiac metabolic disorders and potential molecular mechanisms. Through utilizing clinical samples and high fat.diet-fed mice, we investigated the physiological roles of miR-122 in obesity-related cardiomyopathy. Besides, present study explored the mitochondrial function under exosomal miR-122 stimulation in mouse primary cardiomyocytes. In clinical samples and obese.mice, the circulating level of exosomal miR-122 was positively correlated with cardiac dysfunctional parameters, including reduction in ejection fraction (EF) and increased levels of.NT-proBNP. Human plasma exosomes transported miR-122 into mouse primary cardiomyocytes, and impaired mitochondrial ATP production and oxygen consumption, whereas.miR-122 sponge improved these inhibitory effects. In dietary-induced mice, increased hepatic and circulating exosomal miR-122 deteriorated cardiac structure and functional index,.and inhibited mitochondrial function. Liver-specifc blockage of miR-122 attenuated abnormal cardiac remodeling. Mechanistically, miR-122 directly bound and suppressed mitochondrial protein ADP-ribosylation factor-like 2 (Arl-2) in vitro and in vivo. Knockdown of.Arl-2 abolished the mitochondrial benefts of miR-122 sponge in exosome-treated mouse.primary cardiomyocytes..In conclusions, our present study frstly showed that liver-secreted exosomal.miR-122 played a critical role in the development of metabolic cardiomyopathy, and.miR-122/mitochondrial Arl-2 signaling affected cardiac energy homeostasis.