1. Atherosclerosis-associated endothelial dysfunction is promoted by miR-199a-5p/SIRT1 axis regulated by circHIF1ɑ.
- Author
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Qiao, Shan, Wang, Xing, Li, Haiyun, Zhang, Canling, Wang, Aihua, and Zhang, Shanchao
- Abstract
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. 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. 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. • Vascular atherosclerosis is the most leading cause of cardiovascular or cerebrovascular disorders. It is crucial to identify and develop various diagnostic and treatment strategies to treat atherosclerosis. • Our study aimed to identify the miR-199a-5p/SIRT1 axis regulated by circHIF1ɑ in the pathogenesis of atherosclerosis. • miR-199a-5p could be a potential diagnostic marker for atherosclerosis development and progression, and circHIF1ɑ/miR-199a-5p axis could be used as a potential treatment strategy to treat atherosclerosis. [ABSTRACT FROM AUTHOR]
- Published
- 2023
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