Hsa-miRNA-23a-3p promotes atherogenesis in a novel mouse model of atherosclerosis

Abstract

Of the known regulators of atherosclerosis, miRNAs have been demonstrated to play critical roles in lipoprotein homeostasis and plaque formation. Here, we generated a novel animal model of atherosclerosis by knocking in LDLRW483X in C57BL/6 mice, as the W483X mutation in LDLR is considered the most common newly identified pathogenic mutation in Chinese familial hypercholesterolemia (FH) individuals. Using the new in vivo mouse model combined with a well-established atherosclerotic in vitro human cell model, we identified a novel atherosclerosis-related miRNA, miR-23a-3p, by microarray analysis of mouse aortic tissue specimens and human aortic endothelial cells (HAECs). miR-23a-3p was consistently downregulated in both models, which was confirmed by qPCR. Bioinformatics analysis and further validation experiments revealed that the TNFα-induced protein 3 (TNFAIP3) gene was the key target of miR-23a-3p. The miR-23a-3p-related functional pathways were then analyzed in HAECs. Collectively, the present results suggest that miR-23a-3p regulates inflammatory and apoptotic pathways in atherogenesis by targeting TNFAIP3 through the NF-κB and p38/MAPK signaling pathways. Of the known regulators of atherosclerosis, miRNAs have been demonstrated to play critical roles in lipoprotein homeostasis and plaque formation. Here, we generated a novel animal model of atherosclerosis by knocking in LDLRW483X in C57BL/6 mice, as the W483X mutation in LDLR is considered the most common newly identified pathogenic mutation in Chinese familial hypercholesterolemia (FH) individuals. Using the new in vivo mouse model combined with a well-established atherosclerotic in vitro human cell model, we identified a novel atherosclerosis-related miRNA, miR-23a-3p, by microarray analysis of mouse aortic tissue specimens and human aortic endothelial cells (HAECs). miR-23a-3p was consistently downregulated in both models, which was confirmed by qPCR. Bioinformatics analysis and further validation experiments revealed that the TNFα-induced protein 3 (TNFAIP3) gene was the key target of miR-23a-3p. The miR-23a-3p-related functional pathways were then analyzed in HAECs. Collectively, the present results suggest that miR-23a-3p regulates inflammatory and apoptotic pathways in atherogenesis by targeting TNFAIP3 through the NF-κB and p38/MAPK signaling pathways. Atherosclerosis is a chronic inflammatory disease of the arteries characterized by plaques built up in the vessels (1Hansson G.K. Libby P. Tabas I. Inflammation and plaque vulnerability.J. Intern. Med. 2015; 278: 483-493Crossref PubMed Scopus (484) Google Scholar, 2Sakao S. Taraseviciene-Stewart L. Lee J.D. Wood K. Cool C.D. Voelkel N.F. Initial apoptosis is followed by increased proliferation of apoptosis-resistant endothelial cells.FASEB J. 2005; 19: 1178-1180Crossref PubMed Scopus (234) Google Scholar, 3Tardy Y. Resnick N. Nagel T. Gimbrone Jr., M.A. Dewey Jr., C.F. 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The microarray was then to miRNAs and analysis was to of atherosclerosis-related in the new atherosclerosis mouse model as as in vitro human cell both models, a novel miRNA, miR-23a-3p, was identified that as a key of targeting TNFα-induced protein 3 miR-23a-3p inflammation and endothelial apoptosis through the NF-κB and p38/MAPK pathways. results that the newly identified atherosclerosis-related role in inflammatory pathways. in both and were in with the and of by the of and by the animal and the were generated at the The mutation in the human LDLR gene was generated through the was by The and were in vitro and with The and were into C57BL/6 mouse a The were then cultured with and into the of was of by the N. T. K. T. and of PubMed Scopus Google Scholar). was by and were by the was confirmed by and The atherosclerosis mouse model was at were a cholesterol and of were in the and and were the and as controls were mouse blood was by at the was by at at and at cholesterol and were on a The mouse was the the to the and was with and with specimens were then with in and with The aortic a with to mouse were in the were through a and in were with and of aortic were by on to plaque formation. and were were the and cultured in vascular cell with the endothelial cell and at in with were with miR-23a-3p control TNFAIP3 miR-23a-3p and the to the of cell the was with with of was on the was aortic endothelial cells and mouse aortic tissue specimens and with a was and with a miRNAs the were with a and miRNAs were then with was with the miRNAs in a at and were in with on microarray and analyzed with the and miRNAs were microarray and microarray were in the gene expression miRNAs were in the microarray was as on in the as in at one in the cell model in the mouse were further analysis and expression in were a The gene was then the and control with and were considered to miRNAs with were considered to miRNAs tissue mice, and miRNAs were with mouse microarray and microarray were in the gene expression miRNAs were in the microarray analysis was as cell microarray miRNAs in vitro and in vivo were target gene target in 2015; Crossref PubMed Scopus Google Scholar). miRNAs were further on the regulation of on gene The miRNAs in were as atherosclerosis-related miRNAs targeting atherosclerosis-related were miRNAs to to atherosclerosis were The miRNAs were further by was cells with to the was analysis was in with the shown in were to the gene expression was and was The of and TNFAIP3 were by and into and followed by cells were with and miR-23a-3p were a The apoptosis was with the cells were and with cells were at a of cells and with and were analyzed on with the at a of 3 cells were with miR-23a-3p miR-23a-3p in of and E-selectin were with a human and TNFAIP3 protein cells at a of cells in were with miRNAs followed by TNFAIP3 expression was with the adhesion was with a adhesion at a of in were with followed by cells at 3 cells with were to the endothelial to were with the were and protein were with a were then by and were and with TNFAIP3 and at with the were on a analysis was with were by followed by and was by and and were considered at are a common mutation of the LDLR gene been identified as a pathogenic mutation in Chinese L. Chen L. Wang W. Zhao L.M. Wang of the Chinese W483X mutation in the low-density gene in with familial Full Text Full Text PDF PubMed Scopus Google Scholar). The of LDLR is and on the analysis in the LDLR M. and analysis 2009; PubMed Scopus Google Scholar). a human mouse model of atherosclerosis that the human we generated a LDLR mutation mouse model by the with and as shown in The in the of are in results that the was of and the mutation was by of LDLR and and LDLR and were were and and of and mice, The of LDLR increased the and LDLR and on with shown in and in LDLR were of in LDLR were a lipid with LDLR in and shown on plaques in the aortic was with and LDLR mice, LDLR mice, plaques in the aortic plaque in the aortic of LDLR were to of the of plaque of the aortic was in LDLR with plaques were in LDLR the in the of vascular endothelial cells are to leading to lipid accumulation and foam cell formation (5Li D. Chen H. Romeo F. Sawamura T. Saldeen T. Mehta J.L. Statins modulate oxidized low-density lipoprotein-mediated adhesion molecule expression in human coronary artery endothelial cells: role of LOX-1.J. Pharmacol. Exp. Ther. 2002; 302: 601-605Crossref PubMed Scopus (163) Google Scholar, 6Pirillo A. Norata G.D. Catapano A.L. LOX-1, OxLDL, and atherosclerosis.Mediators Inflamm. 2013; 2013152786 Crossref PubMed Scopus (470) Google Scholar). been to to plaque by endothelial cell apoptosis (4Cancel L.M. Tarbell J.M. The role of apoptosis in LDL transport through cultured endothelial cell monolayers.Atherosclerosis. 2010; 208: 335-341Abstract Full Text Full Text PDF PubMed Scopus (38) Google Scholar, 6Pirillo A. Norata G.D. Catapano A.L. LOX-1, OxLDL, and atherosclerosis.Mediators Inflamm. 2013; 2013152786 Crossref PubMed Scopus (470) Google Scholar, M. K. LDL endothelial cell PubMed Scopus Google Scholar). atherosclerosis-related we in vitro model on HAECs. of were with and cell apoptosis was then analyzed by shown in and cell apoptosis in in a and which at at both and with the inflammatory E-selectin and were increased and with cells results that and the inflammatory that to the of cell at and at and on apoptotic we of experiments to and apoptotic both in vivo and in vitro models, a of miRNAs and the human and and and the human and were by microarray Among human miRNAs downregulated and and mouse miRNAs downregulated and were in the in vitro and in vivo of atherosclerosis, altered expression were in human and and mouse and novel miRNAs to atherosclerosis, a was and in of miRNAs were identified in both models, 3 and downregulated with controls the of J.F. Zhang K. Zhao Y. Chen H. Wei Wang and expression by targeting in Biol. PubMed Scopus Google Scholar), F. C. S. R. A. M. of in atherosclerotic PubMed Scopus Google Scholar), and A. M. 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