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Published on: June 15, 2018
The lncRNA MALAT1 participates in regulating coronary slow flow endothelial dysfunction through the
Cuiting Zhao1, Zhihong Zong2, Qing Zhu1
1Department of Cardiovascular Ultrasound, The First Hospital of China Medical University, Shenyang, China.
Insights
Coronary slow flow (CSF) involves endothelial dysfunction. The long non-coding RNA MALAT1 regulates this dysfunction via the miR-181b-5p-MEF2A-ET-1 pathway, offering a potential new treatment target for CSF.
Area of Science:
- Cardiovascular Biology
- Molecular Medicine
- RNA Biology
Background:
- Coronary slow flow (CSF) is characterized by reduced coronary flow without significant stenosis, primarily caused by endothelial dysfunction.
- The role of long non-coding RNA MALAT1 in CSF-related endothelial dysfunction remains largely unexplored.
Purpose of the Study:
- To investigate the role of MALAT1 in endothelial dysfunction associated with coronary slow flow.
- To elucidate the molecular mechanisms involving MALAT1, miR-181b-5p, MEF2A, and ET-1 in CSF.
Main Methods:
- Coronary angiography, echocardiography, and flow-mediated dilation were performed on 41 CSF patients and 37 controls.
- Human umbilical vein endothelial cells (HUVECs) were used to model CSF-induced endothelial dysfunction.
- Expression levels of MALAT1, miR-181b-5p, MEF2A, and ET-1 were quantified using qRT-PCR and western blotting; cell function was assessed via proliferation and apoptosis assays.
Main Results:
- MALAT1 and ET-1 were elevated, while miR-181b-5p was decreased in CSF patients' plasma, serving as potential CSF biomarkers.
- In CSF-induced HUVECs, MALAT1 upregulation and miR-181b-5p downregulation impaired endothelial function; their modulation reversed these effects.
- MEF2A positively regulated ET-1 expression and contributed to endothelial dysfunction, with MALAT1 acting as a sponge for miR-181b-5p to modulate MEF2A.
Conclusions:
- Endothelial dysfunction is a key feature of coronary slow flow.
- The MALAT1/miR-181b-5p/MEF2A/ET-1 axis is implicated in CSF-induced endothelial dysfunction.
- Targeting MALAT1 presents a promising therapeutic strategy for coronary slow flow treatment.
Background:
Coronary slow flow (CSF) refers to coronary arteries with no obvious stenosis but have slow coronary flow without effective treatment. The main cause of CSF is endothelial dysfunction. The long non-coding RNA (lncRNA) MALAT1 is involved in regulating endothelial dysfunction, but its role in CSF endothelial dysfunction is still unclear.
Methods:
We included 41 CSF patients and 37 controls in the study, who all underwent coronary angiography, echocardiography, and brachial artery flow-mediated dilatation (FMD) examination. Human umbilical vein endothelial cells (HUVECs) stimulated by oxygen-glucose deprivation were used as CSF-induced HUVECs. Plasma endothelin-1 (ET-1) concentrations were determined by enzyme-linked immunosorbent assay (ELISA). The expression levels of MALAT1, miR-181b-5p, myocyte enhancer factor 2A (MEF2A), and ET-1 were measured by qRT-PCR or western blotting. Cell proliferation was determined by 5-ethynyl-2'-deoxyuridine (EdU) and Cell Counting Kit-8 (CCK-8) assays. Apoptosis was examined by flow cytometry. The relationship between miR-181b-5p and MALAT1 or MEF2A was verified by dual-luciferase reporter assay. MEF2A binding directly to the ET-1 promoter region was verified via chromatin immunoprecipitation (ChIP) assay.
Results:
MALAT1 and ET-1 were increased, and miR-181b-5p was decreased in the peripheral blood of the CSF patients, and could be used as predictors of CSF. In the CSF-induced HUVECs, MALAT1 was highly expressed, and MALAT1 knockdown improved endothelial function. In contrast, miR-181b-5p was downregulated in the CSF-induced HUVECs, and miR-181b-5p overexpression improved endothelial function. While MEF2A was highly enriched in CSF-induced HUVECs, MEF2A knockdown reduced ET-1 and increased the endothelial function of CSF-induced HUVECs as a transcriptional regulator of ET-1. MALAT1 modulated MEF2A expression positively by sponging miR-181b-5p.
Conclusions:
Endothelial function is reduced in CSF. MALAT1 participates in regulating CSF endothelial dysfunction through the miR-181b-5p-MEF2A-ET-1 axis, and could provide a new target for CSF treatment.
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