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Induction of Atherosclerotic Plaques Through Activation of Mineralocorticoid Receptors in Apolipoprotein E-deficient Mice
Published on: September 26, 2018
MicroRNA-23a-5p promotes atherosclerotic plaque progression and vulnerability by repressing ATP-binding cassette
Shuai Yang1, Zi-Ming Ye2, Shengcai Chen1
1Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.
Abstract:
Disruption of carotid vulnerable atherosclerotic plaque is responsible for acute ischemic stroke (AIS) and the early detection and intervention approach are greatly limited. Undertaking a microarray of microRNAs (miRNAs) in the plasma of AIS patients with carotid vulnerable plaques, miR-23a-5p was markedly elevated and was positively correlated with the plaque progression and vulnerability. Correspondingly, we found that miR-23a-5p expression was significantly increased in both plasma and macrophages from atherosclerosis mice. Bioinformatics analysis and in vitro knockdown experiments identified that ATP-binding cassette transporter A1/G1 as a novel target of miR-23a-5p. Luciferase reporter assays showed that miR-23a-5p repressed the 3' untranslated regions (UTR) activity of ABCA1/G1. Moreover, functional analyses demonstrated that transfection of miR-23a-5p inhibitor enhanced cholesterol efflux and decreased foam cell formation through upregulating ABCA1/G1 expression levels. Furthermore, long term in vivo systemically delivered miR-23a-5p antagomir significantly increased ABCA1/G1 expression in the aorta of ApoE-/- mice. Importantly, the miR-23a-5p antagomir therapy significantly reduced atherosclerosis progression and promoted plaque stability. Our observations indicate that miR-23a-5p promotes macrophage-derived foam cell formation and might be a key regulator contributing to atherosclerotic plaque progression and vulnerability.
Insights
MicroRNA-23a-5p (miR-23a-5p) promotes vulnerable plaque formation in atherosclerosis by inhibiting cholesterol efflux. Inhibiting miR-23a-5p offers a potential therapeutic strategy to stabilize plaques and prevent stroke.
Area of Science:
- Cardiovascular Biology
- Molecular Medicine
- Biochemistry
Background:
- Vulnerable atherosclerotic plaques in carotid arteries are a primary cause of acute ischemic stroke (AIS).
- Early detection and intervention for vulnerable plaques remain challenging.
- MicroRNAs (miRNAs) play critical roles in regulating cellular processes relevant to atherosclerosis.
Purpose of the Study:
- To investigate the role of specific miRNAs in the development and progression of vulnerable atherosclerotic plaques.
- To identify novel molecular targets and therapeutic strategies for atherosclerosis and AIS.
Main Methods:
- Microarray analysis of plasma miRNAs in AIS patients with vulnerable plaques.
- Expression analysis of miR-23a-5p in plasma and macrophages from atherosclerosis mouse models.
- Bioinformatics analysis and in vitro experiments to identify miR-23a-5p targets.
- Luciferase reporter assays to confirm miR-23a-5p binding to target 3' UTRs.
- In vitro functional assays assessing cholesterol efflux and foam cell formation.
- In vivo studies using ApoE-/- mice treated with miR-23a-5p antagomir.
Main Results:
- miR-23a-5p was significantly elevated in AIS patients with vulnerable plaques and correlated with plaque progression.
- miR-23a-5p expression was increased in plasma and macrophages of atherosclerosis mice.
- ATP-binding cassette transporters A1/G1 (ABCA1/G1) were identified as novel targets of miR-23a-5p.
- miR-23a-5p inhibition enhanced cholesterol efflux and reduced foam cell formation by upregulating ABCA1/G1.
- Systemic delivery of miR-23a-5p antagomir increased ABCA1/G1 expression, reduced atherosclerosis, and promoted plaque stability in vivo.
Conclusions:
- miR-23a-5p is a key regulator in the progression and vulnerability of atherosclerotic plaques.
- miR-23a-5p promotes macrophage-derived foam cell formation.
- Targeting miR-23a-5p with antagomirs represents a promising therapeutic approach for atherosclerosis and stroke prevention.
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