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MiR-199a-3p Restrains Foaming and Inflammation by Regulating RUNX1 in Macrophages
Mingxin Liu1, Yiming Cao2, Yu Hu2
1Department of Cardiology, The First Affiliated Hospital of Jinzhou Medical University, No. 2, Section 5, Renmin Street, Jinzhou, 121001, Liaoning, People's Republic of China. 15640620408@163.com.
Abstract:
MiR-199a-3p was reported decreased in serum of coronary heart disease patients and human atherosclerotic plaques. This study aims to investigate the roles of miR-199a-3p in atherosclerosis (AS). AS was induced in ApoE-/- mice via high fat diet for 12 weeks. Oxidized low density lipoprotein (ox-LDL) was used to induce foaming in RAW264.7 cells. The expression level of miR-199a-3p was decreased in aortas of AS mice and ox-LDL-treated macrophages. Oil red O staining, ELISA, flow cytometry, and western blot results demonstrated that miR-199a-3p mimics restrained ox-LDL-induced lipid accumulation, foaming, and inflammation in RAW264.7 cells, while miR-199a-3p inhibitor played opposite roles. Runt-related transcription factor 1 (RUNX1), a pro-inflammatory factor, was identified as a target of miR-199a-3p, and its expression was downregulated by miR-199a-3p. RUNX1 was increased in macrophages from aortas and peripheral blood of AS mice. Ox-LDL-induced inflammation and lipid accumulation were aggravated by RUNX1, and the effects of miR-199a-3p were antagonized by ectopic expression of RUNX1 in RAW264.7 cells. The phosphorylation of signal transducer and activator of transcription 3 (STAT3) was inhibited by miR-199a-3p and enhanced by RUNX1. In conclusions, we demonstrated that miR-199a-3p alleviated ox-LDL-induced foaming and inflammation by downregulating RUNX1 expression and deactivating STAT3 signaling in macrophages. These findings may provide novel targets for treatment of AS.
Insights
MicroRNA-199a-3p (miR-199a-3p) reduces atherosclerosis by inhibiting lipid accumulation and inflammation. It targets RUNX1, deactivating STAT3 signaling in macrophages, offering potential therapeutic targets for coronary heart disease.
Area of Science:
- Cardiovascular Biology
- Molecular Medicine
- Atherosclerosis Research
Background:
- Coronary heart disease (CHD) is linked to decreased miR-199a-3p levels in patients and atherosclerotic plaques.
- Atherosclerosis (AS) involves lipid accumulation and inflammation in macrophages.
- Understanding the role of microRNAs in AS is crucial for developing new treatments.
Purpose of the Study:
- To investigate the role of miR-199a-3p in the pathogenesis of atherosclerosis.
- To identify the molecular mechanisms by which miR-199a-3p influences macrophage response to oxidized low-density lipoprotein (ox-LDL).
Main Methods:
- Atherosclerosis was induced in ApoE-/- mice using a high-fat diet.
- Macrophage foam cell formation and inflammation were induced by ox-LDL in RAW264.7 cells.
- miR-199a-3p mimics and inhibitors were used to assess its function.
- Target gene validation involved assessing Runt-related transcription factor 1 (RUNX1) and Signal transducer and activator of transcription 3 (STAT3) pathways.
Main Results:
- miR-199a-3p expression was reduced in AS mouse aortas and ox-LDL-treated macrophages.
- miR-199a-3p mimics suppressed ox-LDL-induced lipid accumulation, foam cell formation, and inflammation.
- miR-199a-3p directly targeted and downregulated the pro-inflammatory factor RUNX1.
- RUNX1 aggravated ox-LDL-induced inflammation and lipid accumulation, antagonizing miR-199a-3p effects.
- miR-199a-3p inhibited STAT3 phosphorylation, while RUNX1 enhanced it.
Conclusions:
- miR-199a-3p exerts protective effects against ox-LDL-induced macrophage inflammation and lipid accumulation.
- These effects are mediated by the downregulation of RUNX1 and subsequent deactivation of STAT3 signaling.
- miR-199a-3p represents a potential therapeutic target for atherosclerosis treatment.
