Exosomally derived Y RNA fragment alleviates hypertrophic cardiomyopathy in transgenic mice.
Exosomally derived Y RNA fragment alleviates hypertrophic cardiomyopathy in transgenic mice.
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DOI：
10.1016/j.omtn.2021.04.014
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发表时间：
2021-06-04
期刊：
影响因子：
--
通讯作者：
de Couto G
中科院分区：
文献类型：
--
作者：
Huang F;Na N;Ijichi T;Wu X;Miyamoto K;Ciullo A;Tran M;Li L;Ibrahim A;Marbán E;de Couto G
微球衍生的细胞外泌体（CDCexo）和YF 1（CDCexo衍生的非编码RNA）在心肌梗死和高血压性肥大模型中引发治疗生物活性。在这里，我们测试的假设，YF 1，一个56个核苷酸的Y RNA片段，可以减轻心肌细胞肥大，炎症和纤维化与肥厚型心肌病（HCM）在转基因小鼠窝藏临床相关的突变，心肌肌钙蛋白I（cTnIGly 146）。通过定量PCR，在静脉内（i. v.）输液对于功效研究，将小鼠随机分配以接受静脉内YF 1或媒介物，监测行走和心脏功能，并在4周时处死。YF 1（而不是媒介物）改善了心肌肥厚并减少了心脏肥大和纤维化。同时，中性粒细胞和促炎单核细胞的外周动员减少，浸润心脏的巨噬细胞减少。巨噬细胞的RNA测序显示，YF 1赋予基因表达的实质性和广泛的变化，调节与免疫疾病和炎症反应相关的途径。总之，这些数据表明，YF 1可以逆转与HCM相关的肥大和纤维化信号通路，同时改善功能，提高了YF 1可能成为HCM可行的新型治疗候选物的前景。EV-YF 1是来源于由心球来源的细胞分泌的细胞外囊泡的Y RNA片段。在这里，我们表明YF 1作为合成RNA治疗剂单独递送，可以减轻肥大性心肌病转基因小鼠模型中的肥大、炎症和纤维化。这些作用主要通过巨噬细胞的免疫调节介导。
Cardiosphere-derived cell exosomes (CDCexo) and YF1, a CDCexo-derived non-coding RNA, elicit therapeutic bioactivity in models of myocardial infarction and hypertensive hypertrophy. Here we tested the hypothesis that YF1, a 56-nucleotide Y RNA fragment, could alleviate cardiomyocyte hypertrophy, inflammation, and fibrosis associated with hypertrophic cardiomyopathy (HCM) in transgenic mice harboring a clinically relevant mutation in cardiac troponin I (cTnIGly146). By quantitative PCR, YF1 was detectable in bone marrow, spleen, liver, and heart 30 min after intravenous (i.v.) infusion. For efficacy studies, mice were randomly allocated to receive i.v. YF1 or vehicle, monitored for ambulatory and cardiac function, and sacrificed at 4 weeks. YF1 (but not vehicle) improved ambulation and reduced cardiac hypertrophy and fibrosis. In parallel, peripheral mobilization of neutrophils and proinflammatory monocytes was decreased, and fewer macrophages infiltrated the heart. RNA-sequencing of macrophages revealed that YF1 confers substantive and broad changes in gene expression, modulating pathways associated with immunological disease and inflammatory responses. Together, these data demonstrate that YF1 can reverse hypertrophic and fibrotic signaling pathways associated with HCM, while improving function, raising the prospect that YF1 may be a viable novel therapeutic candidate for HCM. EV-YF1 is a Y RNA fragment derived from extracellular vesicles that are secreted by cardiosphere-derived cells. Here we show that YF1, delivered on its own as a synthetic RNA therapeutic, attenuates hypertrophy, inflammation, and fibrosis in a transgenic mouse model of hypertrophic cardiomyopathy. These effects are mediated primarily through the immunomodulation of macrophages.
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影响因子：
3.5
作者：
Grijalvo S;Alagia A;Jorge AF;Eritja R
通讯作者：
Eritja R
影响因子：
37.8
作者：
de Couto G;Gallet R;Cambier L;Jaghatspanyan E;Makkar N;Dawkins JF;Berman BP;Marbán E
通讯作者：
Marbán E
影响因子：
3.3
作者：
Cheng K;Malliaras K;Li TS;Sun B;Houde C;Galang G;Smith J;Matsushita N;Marbán E
通讯作者：
Marbán E
DOI：
10.1161/atvbaha.119.313115
发表时间：
2019-10-01
影响因子：
8.7
作者：
de Couto, Geoffrey;Jaghatspanyan, Ervin;Marban, Eduardo
通讯作者：
Marban, Eduardo
影响因子：
28.1
作者：
Marban, Eduardo
通讯作者：
Marban, Eduardo