拮抗剂
小RNA
细胞保护
基因敲除
心肌梗塞
缺氧(环境)
医学
基因沉默
荧光素酶
活性氧
内科学
缺血
下调和上调
转染
癌症研究
心功能曲线
药理学
心力衰竭
心室重构
心脏病学
细胞生物学
生物
细胞凋亡
细胞培养
化学
氧化应激
氧气
有机化学
生物化学
遗传学
基因
作者
Yimin Xiao,Yanxia Zhang,Yueqiu Chen,Jingjing Li,Zihan Zhang,Yimin Sun,Han Shen,Zhen-Ao Zhao,Zan Huang,Wencheng Zhang,Weiqian Chen,Zhenya Shen
出处
期刊:Human Gene Therapy
[Mary Ann Liebert]
日期:2019-03-01
卷期号:30 (3): 286-301
被引量:50
摘要
Follistatin-like 1 (Fstl1) protects cardiomyocytes from a broad spectrum of pathologic injuries including myocardial infarction (MI). It is worthy of note that although cardiac Fstl1 is elevated in post-MI microenvironment, its cardioprotective role is still restricted to a limited extent considering the frequency and severity of adverse cardiac remodeling following MI. We therefore propose that intrinsic Fstl1-suppressing microRNA (miRNA) may exist in the heart and its neutralization may further facilitate post-MI recovery. Here, miR-9-5p is predicted as one of the potential Fstl1-targeting miRNAs whose expression is decreased in ischemic myocardium and reversely correlated with Fstl1. Luciferase activity assay further validated Fstl1 as a direct target of miR-9-5p. In addition, forced expression of miR-9-5p in H9c2 cells is concurrent with diminished expression of Fstl1 and vice versa. Importantly, transfection of miR-9-5p mimics in hypoxic H9c2 cells exacerbates cardiac cell death, lactate dehydrogenase release, reactive oxygen species accumulation, and malonyldialdehyde concentration. More importantly, in vivo silencing of miR-9-5p by a specific antagomir in a murine acute MI model effectively preserves post-MI heart function with attenuated fibrosis and inflammatory response. Further studies demonstrated that antagomir treatment stabilizes Fstl1 expression as well as blocks cardiac cell death and reactive oxygen species generation in both ischemia-challenged hearts and hypoxia-treated cardiomyoblasts. Finally, cytoprotection against hypoxic challenge by miR-9-5p inhibitor is partially reversed by knockdown of Fstl1, indicating a novel role of miR-9-5p/Fstl1 axis in survival defense against hypoxic challenge. In summary, these findings identified miR-9-5p as a mediator of hypoxic injury in cardiomyoblasts and miR-9-5p suppression prevents cardiac remodeling after acute MI, providing a potential strategy for early treatment against MI.
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