Atherosclerosis-associated endothelial dysfunction is promoted by miR-199a-5p/SIRT1 axis regulated by circHIF1ɑ
Shan Qiao1, Xing Wang2, Haiyun Li3
1Department of Neurology, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Shandong First Medical University, Jinan, China; Department of Neurology, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan, China; Department of Medical Genetics, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, China; Shandong Laibo Biotechnology Co., Ltd, China.
Insights
MicroRNA-199a-5p plays a key role in atherosclerosis by damaging endothelial cells. Targeting the circHIF1ɑ/miR-199a-5p/SIRT1 pathway offers a new therapeutic strategy for atherosclerosis.
Area of Science:
- Cardiovascular Biology
- Molecular Medicine
- RNA Biology
Background:
- Atherosclerosis (AS) is a chronic inflammatory disease driven by hyperlipidemia, leading to endothelial dysfunction and increased atherothrombotic risk.
- Ectopic microRNA-199a-5p (miR-199a-5p) is implicated in endothelial injury, but its function within the AS competitive endogenous RNA (CeRNA) network remains unclear.
Purpose of the Study:
- To investigate the role of miR-199a-5p in the pathogenesis of atherosclerosis.
- To elucidate the molecular mechanisms underlying miR-199a-5p-mediated endothelial dysfunction in AS.
- To identify potential therapeutic targets within the identified regulatory network.
Main Methods:
- Construction of a high-fat diet (HFD)-induced apoE-/- mouse model of atherosclerosis and in vitro endothelial cell (EC) injury models using ox-LDL.
- Assessment of miR-199a-5p expression in aorta tissue, ECs, and plasma extracellular vesicles (EVs) from AS patients.
- Gain- and loss-of-function studies to evaluate the impact of miR-199a-5p on EC proliferation, motility, and neovascularization.
- Mechanistic investigations involving immunohistochemistry, immunofluorescence, and assays to analyze the FOXO signaling pathway, SIRT1, and circHIF1ɑ interactions.
Main Results:
- miR-199a-5p was found to be overexpressed in AS mouse models, ox-LDL-treated ECs, and plasma EVs from cerebral AS patients.
- Silencing miR-199a-5p significantly attenuated atherosclerotic progression in mice.
- miR-199a-5p overexpression exacerbated ox-LDL-induced EC dysfunction, while circHIF1ɑ sponged miR-199a-5p to restore EC function by regulating SIRT1 expression via the FOXO signaling pathway.
Conclusions:
- The study reveals a critical role for the circHIF1ɑ/miR-199a-5p/SIRT1 axis in AS pathogenesis.
- This regulatory pathway represents a novel therapeutic target for the treatment of atherosclerosis.
Background And Aims:
Atherosclerosis (AS) is a chronic inflammatory disease that damages the arterial wall as a result of hyperlipidemia and causes endothelial cell dysfunction, which increases the risk of atherothrombotic events. Multiple pathological conditions have shown ectopic miR-199a-5p levels to cause endothelial injury, but its role in the AS competitive endogenous RNA (CeRNA) network is still unknown.
Methods And Results:
The high-fat diet (HFD) apoE-/- mouse model was constructed in vivo, and ECs were cultured under ox-LDL treatment to induce EC injury in vitro. Immunohistochemistry and immunofluorescence staining were used to assess the effect of miR-199a-5p on the macrophage, SMC, collagen content, and endothelial coverage in the artery wall of mouse model. miR-199a-5p level was validated to be overexpression in the aorta tissue of HFD apoE-/- mice and in the ox-LDL-treated ECs, and even in the plasma EVs of the patients with cerebral AS. Silencing of miR-199a-5p significantly attenuated atherosclerotic progress in HFD apoE-/- mice, and the gain/loss-of-function assay indicated that miR-199a-5p overexpression aggravated ox-LDL-induced disabilities of endothelial proliferation, motility, and neovascularization based on cell counting kit-8 assay, transwell assay and matrigel assay. Mechanistically, miR-199a-5p prevented EC activation by activating the FOXO signaling pathway by targeting SIRT1. Additionally, circular RNA (circRNA) circHIF1ɑ was identified as having a low expression in the ox-LDL-treated EC and mediated SIRT1 expression via sponging miR-199a-5p to rescue ox-LDL-induced EC injury.
Conclusions:
Our study demonstrated the vital role of miR-199a-5p/SIRT1 axis regulated by circHIF1ɑ in AS pathogenesis and provided novel effective targets for AS treatment.
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