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Published on: February 20, 2019
miR-195-3p alleviates homocysteine-mediated atherosclerosis by targeting IL-31 through its epigenetics modifications
Jiantuan Xiong1,2,3, Fang Ma1,2,3, Ning Ding1,2,3
1School of Basic Medical Sciences, Ningxia Medical University, Yinchuan, China.
Abstract:
Atherosclerosis is a serious age-related disease, which has a tremendous impact on health care globally. Macrophage inflammation is crucial for the initiation and progression of atherosclerosis, and microRNAs (miRNAs) recently have emerged as potent modulators of inflammation, while the underlying mechanisms of its involvement in homocysteine (Hcy)-mediated macrophage inflammation of atherosclerosis remain largely unknown. Here, we demonstrated that elevated Hcy inhibits the expression of miR-195-3p, which in turn enhances IL-31 expression and thereby causes the secretion of macrophages pro-inflammatory factors IL-1β, IL-6 and TNF-α and accelerate atherosclerosis. Furthermore, we identified that Hcy can induce DNA hypermethylation and H3K9 deacetylation of miR-195-3p promoter due to the increased the binding of DNMT3a and HDAC11 at its promoter. More importantly, Sp1 interacts with DNMT3a suppressed the binding of HDAC11 at miR-195-3p promoter and promoted its transcription. In summary, our results revealed a novel mechanism that transcriptional and epigenetic regulation of miR-195-3p inhibits macrophage inflammation through targeting IL-31, which provides a candidate diagnostic marker and novel therapeutic target in cardiovascular diseases induced by Hcy.
Insights
Elevated homocysteine (Hcy) triggers inflammation in atherosclerosis by suppressing miR-195-3p, leading to increased IL-31 and pro-inflammatory factors. This epigenetic regulation offers a new therapeutic target for cardiovascular diseases.
Area of Science:
- Cardiovascular Biology
- Epigenetics
- Molecular Medicine
Background:
- Atherosclerosis is a major age-related disease driven by macrophage inflammation.
- MicroRNAs (miRNAs) are key regulators of inflammation, but their role in homocysteine (Hcy)-induced atherosclerosis is unclear.
Purpose of the Study:
- To elucidate the mechanism of Hcy-mediated macrophage inflammation in atherosclerosis.
- To investigate the role of miR-195-3p in this process.
Main Methods:
- Analysis of miR-195-3p expression in Hcy-treated macrophages.
- Investigation of epigenetic modifications (DNA methylation, histone deacetylation) at the miR-195-3p promoter.
- Assessment of the interaction between Sp1, DNMT3a, and HDAC11.
Main Results:
- Elevated Hcy downregulates miR-195-3p expression.
- Suppressed miR-195-3p enhances IL-31, promoting secretion of IL-1β, IL-6, and TNF-α, thus accelerating atherosclerosis.
- Hcy induces DNA hypermethylation and H3K9 deacetylation of the miR-195-3p promoter via DNMT3a and HDAC11.
- Sp1 interaction with DNMT3a modulates HDAC11 binding and promotes miR-195-3p transcription.
Conclusions:
- A novel mechanism of transcriptional and epigenetic regulation of miR-195-3p inhibiting macrophage inflammation via IL-31 targeting is revealed.
- miR-195-3p serves as a potential diagnostic marker and therapeutic target for Hcy-induced cardiovascular diseases.
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