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Cited by 99MicroRNA in disease regulationAtherosclerosis and Cardiovascular DiseasesCholesterol and Lipid Metabolism

MicroRNA-16 suppresses the activation of inflammatory macrophages in atherosclerosis by targeting PDCD4

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LIANG, XUE, XU, ZHAO, YUAN, MENG, ZHANG, YUE, ZHAO, BO, WANG, JUNQIAN, ZHANG, AIXUE, LI, GUANGPING·2016·International Journal of Molecular Medicine
DOI 10.3892/ijmm.2016.2497PMC PMC4790696
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Abstract

Programmed cell death 4 (PDCD4) is involved in a number of bioprocesses, such as apoptosis and inflammation. However, its regulatory mechanisms in atherosclerosis remain unclear. In this study, we investigated the role and mechanisms of action of PDCD4 in high-fat diet-induced atherosclerosis in mice and in foam cells (characteristic pathological cells in atherosclerotic lesions) derived from ox-LDL-stimulated macrophages. MicroRNA (miR)-16 was predicted to bind PDCD4 by bioinformatics analysis. In the mice with atherosclerosis and in the foam cells, PDCD4 protein expression (but not the mRNA expression) was enhanced, while that of miR‑16 was reduced. Transfection with miR‑16 mimic decreased the activity of a luciferase reporter containing the 3' untranslated region (3'UTR) of PDCD4 in the macrophage-derived foam cells. Conversely, treatment with miR‑16 inhibitor enhanced the luciferase activity. However, by introducing mutations in the predicted binding site located in the 3'UTR of PDCD4, the miR‑16 mimic and inhibitor were unable to alter the level of PDCD4, suggesting that miR‑16 is a direct negative regulator of PDCD4 in atherosclerosis. Furthermore, transfection wtih miR‑16 mimic and siRNA targeting PDCD4 suppressed the secretion and mRNA expression of pro-inflammatory factors, such as interleukin (IL)-6 and tumor necrosis factor-α (TNF‑α), whereas it enhanced the secretion and mRNA expression of the anti-inflammatory factor, IL-10. Treatment with miR‑16 inhibitor exerted the opposite effects. In addition, the phosphorylation of p38 and extracellular signal-regulated kinase (ERK), and nuclear factor-κB (NF-κB) expression were altered by miR‑16. In conclusion, our data demonstrate that the targeting of PDCD4 by miR‑16 may suppress the activation of inflammatory macrophages though mitogen-activated protein kinase (MAPK) and NF-κB signaling in atherosclerosis; thus, PDCD4 may prove to be a potential therapeutic target in the treatment of atherosclerosis.

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  • Besides miR21, many other microRNAs such as miR182, miR16, miR150, and miR499 target PDCD4 mRNA down-regulating PDCD4 expression in different cellular systems.

    “Besides miR21, many other kinds of microRNA such as miR182, miR16, miR150, miR499 and other microRNAs has been shown to target the PDCD4 mRNA down-regulating PDCD4 expression in different cellular systems [58,59,60,61].”

    From Control Mechanisms of the Tumor Suppressor PDCD4: Expression and Functions (2019) · cites this paper as [59]

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Authors
LIANG, X., XU, Z., YUAN, M., ZHANG, Y., ZHAO, B., WANG, J., ZHANG, A., & LI, G.
Affiliations
Second Hospital of Tianjin Medical University (CN)
Corresponding author
LI, GUANGPING
ORCID
Venue
International Journal of Molecular Medicine
Publisher
Spandidos Publications
Published
2016-02-22
Volume
37
Issue
4
Pages
967-975
ISSN
  • 1107-3756 (ISSN-L)
  • 1791-244X
DOI
10.3892/ijmm.2016.2497
PMC
PMC4790696
OpenAlex
W2276538703
Cited by
99
References
37
Citations by year
2026: 5 · 2025: 9 · 2024: 8 · 2023: 10 · 2022: 12 · 2021: 14 · 2020: 15 · 2019: 11 · 2018: 7 · 2017: 5 · 2016: 3
FWCI
3.61
Type
journal article
Language
en
Open access
Licence
cc-by-nc-nd
Locations
  • International Journal of Molecular Medicine (publishedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
Funders
  • China Postdoctoral Science Foundation
  • Specialized Research Fund for the Doctoral Program of Higher Education of China
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › MicroRNA in disease regulation
  • Life Sciences › Immunology and Microbiology › Immunology › Atherosclerosis and Cardiovascular Diseases
  • Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
Keywords
miR-16, PDCD4, atherosclerosis, inflammatory macrophages, foam cells, high-fat diet, oxidized LDL, MAPK signaling, NF-κB signaling, p38 MAPK, ERK, interleukin-6, TNF-α, IL-10, 3' untranslated region, therapeutic target
MeSH terms
RAW 264.7 Cells, Animals, Foam Cells, Inflammation, Lipoproteins, LDL, Macrophages, Male, Mice, Inbred C57BL, Cytokines, NF-kappa B, RNA-Binding Proteins, MicroRNAs, Atherosclerosis, Apoptosis Regulatory Proteins, Mice

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