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Interleukin-35 Mitigates ox-LDL-Induced Proatherogenic Effects via Modulating miRNAs Associated with Coronary Artery
Shipra Bhansali1,2, Amit Kumar Yadav2, Chetan Bakshi2
1Department of Endocrinology, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, India.
Purpose:
Recent emergence of miRNAs as important regulators of processes involving lesion formation and regression has highlighted miRNAs as potent therapeutic targets for the treatment of atherosclerosis. Few studies have reported the atheroprotective role of IL-35, a novel immunosuppressive and anti-inflammatory cytokine; however, miRNA-dependent regulation underlying the anti-atherosclerotic potential of IL-35 remains elusive.
Methods:
THP-1 macrophages were incubated with human recombinant IL-35 (rIL-35) either in the presence or absence of ox-LDL. qRT-PCR was conducted to validate the expression levels of previously identified miRNAs including miR-197-5p, miR-4442, miR-324-3p, miR-6879-5p, and miR-6069 that were differentially expressed in peripheral blood mononuclear cells of coronary artery disease (CAD) patients vs. controls. Additionally, bioinformatic analysis was performed to predict miRNA-associated targets and their corresponding functional significance in CAD.
Results:
Exogenous IL-35 significantly decreased the average area of ox-LDL-stimulated macrophages, indicating the inhibitory effect of IL-35 on lipid-laden foam cell formation. Furthermore, rIL-35 treatment alleviated the ox-LDL-mediated atherogenic effects by modulating the expression levels of aforementioned CAD-associated miRNAs in the cultured macrophages. Moreover, functional enrichment analysis of these miRNA-related targets revealed their role in the molecular processes affecting different stages of atheroslerotic plaque development, such as macrophage polarization, T cell suppression, lipoprotein metabolism, foam cell formation, and iNOS-mediated inflammation.
Conclusion:
Our observations uncover the novel role of IL-35 as an epigenetic modifier as it influences the expression level of miRNAs implicated in the pathogenesis of atherosclerosis. Thus, IL-35 cytokine therapy-mediated miRNA targeting could be an effective therapeutic strategy against the development of early atheromas in asymptomatic high-risk CAD patients.
Insights
Interleukin-35 (IL-35) reduces atherosclerosis by epigenetically modifying microRNAs (miRNAs) involved in lesion development. This cytokine therapy offers a potential strategy for treating early atherosclerosis in high-risk patients.
Area of Science:
- Cardiovascular Biology
- Immunology
- Molecular Medicine
Background:
- MicroRNAs (miRNAs) are key regulators in atherosclerosis development and regression.
- Interleukin-35 (IL-35) is an anti-inflammatory cytokine with potential atheroprotective effects.
- The miRNA-dependent mechanisms of IL-35's anti-atherosclerotic action are not well understood.
Purpose of the Study:
- To investigate the role of IL-35 in regulating miRNAs associated with atherosclerosis.
- To explore the therapeutic potential of IL-35 in modulating miRNA expression for atherosclerosis treatment.
Main Methods:
- THP-1 macrophages were treated with recombinant IL-35 (rIL-35) and oxidized low-density lipoprotein (ox-LDL).
- Quantitative reverse transcription polymerase chain reaction (qRT-PCR) was used to measure miRNA expression levels.
- Bioinformatic analysis predicted miRNA targets and their functional roles in coronary artery disease (CAD).
Main Results:
- IL-35 significantly inhibited ox-LDL-induced foam cell formation in macrophages.
- rIL-35 modulated the expression of specific CAD-associated miRNAs in macrophages.
- Functional analysis indicated these miRNAs are involved in key atherosclerotic processes, including inflammation and lipid metabolism.
Conclusions:
- IL-35 acts as an epigenetic modifier by influencing atherosclerosis-related miRNA expression.
- Targeting miRNAs with IL-35 cytokine therapy may be a viable strategy for preventing early atherosclerosis.
- This approach could benefit asymptomatic, high-risk CAD patients.
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