Sacubitril/Valsartan Improves Cardiac Function and Decreases Myocardial Fibrosis Via Downregulation of Exosomal miR-181a in a Rodent Chronic Myocardial Infarction Model.
Sacubitril/Valsartan Improves Cardiac Function and Decreases Myocardial Fibrosis Via Downregulation of Exosomal miR-181a in a Rodent Chronic Myocardial Infarction Model.
复制标题
DOI：
10.1161/jaha.119.015640
复制
发表时间：
2020-07-07
影响因子：
5.4
通讯作者：
Yang PC
中科院分区：
文献类型：
--
作者：
Vaskova E;Ikeda G;Tada Y;Wahlquist C;Mercola M;Yang PC
胞外体是小的胞外小泡，起细胞间信使和效应器的作用。胞外体货物含有受调节的小分子，包括miRNAs、mRNAs、lncRNAs和小肽，它们可以被不同的病理刺激调节到细胞中。药物治疗的主要作用机制之一可能是改变外切体的生产和/或含量。我们利用体外培养的人多能干细胞来源的心肌细胞，在常氧和低氧损伤模型下，研究了奈普利辛抑制剂/血管紧张素受体阻滞剂、萨舒比利/valsartan和valsartan单独对外切体产生和含量的影响，并利用在体心肌缺血损伤啮齿动物模型进行了生理学相关性评估。我们证明了萨舒比利/valsartan和valsartan单独处理导致体外诱导的多能干细胞来源的心肌细胞在两种条件下以及在体内的大鼠血浆中都增加了外切体的产生。对这些外切体的下一代测序显示，在萨舒比利/valsartan治疗组，RNO-miR-181a的表达下调。利用慢性啮齿动物心肌损伤模型进行的体内研究表明，miR-181a对心功能有良好的影响。随后，免疫组织化学和分子生物学研究表明，miR-181a的下调可减轻心肌纤维化和肥大，恢复心肌梗死后受损的啮齿动物心脏。我们证明，萨舒比利/valsartan多效性作用的另一个作用机制可能是通过调节外体有效载荷中miRNA的表达水平来实现的。
Exosomes are small extracellular vesicles that function as intercellular messengers and effectors. Exosomal cargo contains regulatory small molecules, including miRNAs, mRNAs, lncRNAs, and small peptides that can be modulated by different pathological stimuli to the cells. One of the main mechanisms of action of drug therapy may be the altered production and/or content of the exosomes. We studied the effects on exosome production and content by neprilysin inhibitor/angiotensin receptor blockers, sacubitril/valsartan and valsartan alone, using human‐induced pluripotent stem cell‐derived cardiomyocytes under normoxic and hypoxic injury model in vitro, and assessed for physiologic correlation using an ischemic myocardial injury rodent model in vivo. We demonstrated that the treatment with sacubitril/valsartan and valsartan alone resulted in the increased production of exosomes by induced pluripotent stem cell‐derived cardiomyocytes in vitro in both conditions as well as in the rat plasma in vivo. Next‐generation sequencing of these exosomes exhibited downregulation of the expression of rno‐miR‐181a in the sacubitril/valsartan treatment group. In vivo studies employing chronic rodent myocardial injury model demonstrated that miR‐181a antagomir has a beneficial effect on cardiac function. Subsequently, immunohistochemical and molecular studies suggested that the downregulation of miR‐181a resulted in the attenuation of myocardial fibrosis and hypertrophy, restoring the injured rodent heart after myocardial infarction. We demonstrate that an additional mechanism of action of the pleiotropic effects of sacubitril/valsartan may be mediated by the modulation of the miRNA expression level in the exosome payload.