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Published on: June 3, 2018
MiR-150 Attenuates Maladaptive Cardiac Remodeling Mediated by Long Noncoding RNA MIAT and Directly Represses
Tatsuya Aonuma1,2, Bruno Moukette1, Satoshi Kawaguchi1
1Department of Anatomy, Cell Biology, and Physiology (T.A., B.M., S.K., N.P.B., M.N.S., I.-m.K.), Indiana University School of Medicine, Indianapolis.
Background:
MicroRNA-150 (miR-150) plays a protective role in heart failure (HF). Long noncoding RNA, myocardial infarction-associated transcript (MIAT) regulates miR-150 function in vitro by direct interaction. Concurrent with miR-150 downregulation, MIAT is upregulated in failing hearts, and gain-of-function single-nucleotide polymorphisms in MIAT are associated with increased risk of myocardial infarction (MI) in humans. Despite the correlative relationship between MIAT and miR-150 in HF, their in vivo functional relationship has never been established, and molecular mechanisms by which these 2 noncoding RNAs regulate cardiac protection remain elusive.
Methods:
We use MIAT KO (knockout), Hoxa4 (homeobox a4) KO, MIAT TG (transgenic), and miR-150 TG mice. We also develop DTG (double TG) mice overexpressing MIAT and miR-150. We then use a mouse model of MI followed by cardiac functional, structural, and mechanistic studies by echocardiography, immunohistochemistry, transcriptome profiling, Western blotting, and quantitative real-time reverse transcription-polymerase chain reaction. Moreover, we perform expression analyses in hearts from patients with HF. Lastly, we investigate cardiac fibroblast activation using primary adult human cardiac fibroblasts and in vitro assays to define the conserved MIAT/miR-150/HOXA4 axis.
Results:
Using novel mouse models, we demonstrate that genetic overexpression of MIAT worsens cardiac remodeling, while genetic deletion of MIAT protects hearts against MI. Importantly, miR-150 overexpression attenuates the detrimental post-MI effects caused by MIAT. Genome-wide transcriptomic analysis of MIAT null mouse hearts identifies Hoxa4 as a novel downstream target of the MIAT/miR-150 axis. Hoxa4 is upregulated in cardiac fibroblasts isolated from ischemic myocardium and subjected to hypoxia/reoxygenation. HOXA4 is also upregulated in patients with HF. Moreover, Hoxa4 deficiency in mice protects the heart from MI. Lastly, protective actions of cardiac fibroblast miR-150 are partially attributed to the direct and functional repression of profibrotic Hoxa4.
Conclusions:
Our findings delineate a pivotal functional interaction among MIAT, miR-150, and Hoxa4 as a novel regulatory mechanism pertinent to ischemic HF.
Insights
Myocardial infarction-associated transcript (MIAT) worsens heart failure, while its deletion protects the heart. MicroRNA-150 (miR-150) counteracts MIAT effects by targeting HOXA4, revealing a novel axis for ischemic heart failure treatment.
Area of Science:
- Molecular Biology
- Cardiovascular Research
- Genetics
Background:
- MicroRNA-150 (miR-150) exhibits cardioprotective effects in heart failure (HF).
- Long noncoding RNA myocardial infarction-associated transcript (MIAT) interacts with miR-150 in vitro.
- MIAT is upregulated and associated with increased myocardial infarction (MI) risk in HF patients, while miR-150 is downregulated.
Purpose of the Study:
- To establish the in vivo functional relationship between MIAT and miR-150 in the context of heart failure.
- To elucidate the molecular mechanisms underlying the regulation of cardiac protection by MIAT and miR-150.
- To investigate the role of the MIAT/miR-150 axis in cardiac fibroblast activation and ischemic heart failure.
Main Methods:
- Utilized genetically modified mouse models: MIAT knockout (KO), HOXA4 KO, MIAT transgenic (TG), and miR-150 TG mice.
- Developed double transgenic (DTG) mice overexpressing both MIAT and miR-150.
- Conducted post-MI cardiac functional, structural, and mechanistic studies, including echocardiography, transcriptomics, and Western blotting, alongside analyses in human HF patient hearts and primary cardiac fibroblasts.
Main Results:
- Genetic overexpression of MIAT exacerbated cardiac remodeling and MI outcomes, whereas MIAT deletion conferred protection.
- Overexpression of miR-150 attenuated the detrimental effects of MIAT post-MI.
- Identified HOXA4 as a novel downstream target of the MIAT/miR-150 axis; HOXA4 upregulation in cardiac fibroblasts and human HF hearts was observed, and its deficiency protected against MI.
Conclusions:
- Delineated a novel regulatory mechanism involving MIAT, miR-150, and HOXA4 in ischemic heart failure.
- Demonstrated that miR-150 exerts protective effects partly through direct repression of profibrotic HOXA4.
- The MIAT/miR-150/HOXA4 axis represents a significant pathway in the pathophysiology of ischemic heart failure.
