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The Mechanism Of MicroRNA-454-3p In Regulating TRPC3 In Aortic Atherosclerosis

Posted on:2023-03-12Degree:DoctorType:Dissertation
Country:ChinaCandidate:L M LiaoFull Text:PDF
GTID:1524306902989369Subject:Cardiovascular internal medicine
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BackgroundAtherosclerosis(AS)is a chronic multifactorial disease with the formation of fibrolipid plaques in the arterial wall,which can lead to acute myocardial infarction,stroke and peripheral vascular stenosis and occlusion.Endothelial cell(EC)apoptosis is a key factor in the pathogenesis of atherosclerosis,which is prone to endothelial dysfunction,atherosclerotic plaque instability and thrombosis.The prevention of endothelial apoptosis and stabilizing endothelial barrier function as a promising new treatment for atherosclerosis has received extensive attention.MicroRNA-454-3p can act on a variety of tissue cells such as epithelial cells and macrophages,and the formation of atherosclerosis is closely related to endothelial cells and macrophages.The research of microRNA-454-3p in endothelial cells has not been reported yet,and will fill the gap in related fields.ObjectionThis article aims to explore the relationship between microRNA-454-3p and human aortic endothelial cells or mouse aortic tissue to reveal the relevant mechanism of atherosclerosis,and explore the potential target of atherosclerosis treatment.Content and Methods1.MicroRNA-454-3p expression and the effects of microRNA-454-3p interfering/overexpression on endothelial apoptosis in the process of atherosclerosis were studied by western blotting,RT-qPCR,apoptosis analysis,cell viability assay(CCK-8),LDH and Caspase3 viability assay.2.Using the biological prediction software TargetScan and miRDB to predict the potential target genes of microRNA-454-3p and find the possible binding sites of microRNA-454-3p in the 3’-non-translational region(3’-UTR)of TRPC3,the double luciferase report showed that microRNA-454-3p could directly target TRPC3.And investigate the effect of microRNA-454-3p on endothelial cell apoptosis and apoptosis during the formation of atherosclerosis by inhibiting TRPC3 expression.3.The effects of microRNA-454-3p on aortic atherosclerotic plaque,apoptosis,tissue injury and TRPC3 expression in the process of aortic atherosclerosis in mice were studied by H&E staining,apoptosis analysis and western blotting.Results1.The expression of microRNA-454-3p and cell viability in human aortic endothelial cells decreased,and endothelial apoptosis elevated with the increase of ox-LDL(oxidized low-density lipoprotein)administration concentration or the expanding actuation duration.MicroRNA-454-3p interfering can promote the apoptosis of endothelial cells.Overexpression of microRNA-454-3p significantly inhibited endothelial cell apoptosis induced by ox-LDL treatment.2.Identify TRPC3 as a direct targeting gene for microRNA-454-3p.TRPC3 inhibits the anti-apoptotic effect of microRNA-454-3p on endothelial cells.TRPC3 inhibits the effect of microRNA-454-3p resistance to ox-LDL-mediated apoptosis in endothelial cells.3.In vivo mouse experiments it confirmed that microRNA-454-3p could regulate TRPC3 to inhibit the formation of aortic atherosclerotic plaques and aortic endothelial cell apoptosis.Conclusion1.Ox-LDL significantly downregulated microRNA-454-3p expression in human aortic endothelial cells(HAECs)in a concentration-dependent or time-dependent manner.MicroRNA-454-3p can be used as a protective factor of endothelial cell damage and apoptosis induced by ox-LDL.2.Transient receptor potential canonical 3(TRPC3)is a direct target for microRNA-454-3p.In addition,TRPC3 overexpression also reversed the anti-apoptotic effect of microRNA-454-3p during atherosclerosis formation.3.MicroRNA-454-3p could regulate TRPC3 to inhibit the formation of aortic atherosclerotic plaques and aortic endothelial cell apoptosis in the mouse.
Keywords/Search Tags:MicroRNA-454-3p, TRPC3, Endothelial apoptosis, Atherosclerosis
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