title: Pitavastatin Differentially Modulates MicroRNA-Associated Cholesterol Transport Proteins in Macrophages.
abstract: There is emerging evidence identifying microRNAs (miRNAs) as mediators of statin-induced cholesterol efflux, notably through the ATP-binding cassette transporter A1 (ABCA1) in macrophages. The objective of this study was to assess the impact of an HMG-CoA reductase inhibitor, pitavastatin, on macrophage miRNAs in the presence and absence of oxidized-LDL, a hallmark of a pro-atherogenic milieu. Treatment of human THP-1 cells with pitavastatin prevented the oxLDL-mediated suppression of miR-33a, -33b and -758 mRNA in these cells, an effect which was not uniquely attributable to induction of SREBP2. Induction of ABCA1 mRNA and protein by oxLDL was inhibited (30%) by pitavastatin, while oxLDL or pitavastatin alone significantly induced and repressed ABCA1 expression, respectively. These findings are consistent with previous reports in macrophages. miRNA profiling was also performed using a miRNA array. We identified specific miRNAs which were up-regulated (122) and down-regulated (107) in THP-1 cells treated with oxLDL plus pitavastatin versus oxLDL alone, indicating distinct regulatory networks in these cells. Moreover, several of the differentially expressed miRNAs identified are functionally associated with cholesterol trafficking (six miRNAs in cells treated with oxLDL versus oxLDL plus pitavastatin). Our findings indicate that pitavastatin can differentially modulate miRNA in the presence of oxLDL; and, our results provide evidence that the net effect on cholesterol homeostasis is mediated by a network of miRNAs.
authors.affiliation: Department of Cell and Developmental Biology, Weill Medical College of Cornell University, 1300 York Ave, New York, New York, 10065, United States of America.|Department of Genetic Medicine, Weill Medical College of Cornell University, 1300 York Ave, New York, New York, 10065, United States of America.
authors.forename: Haijun
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Department of Pathology and Laboratory Medicine, Weill Medical College of Cornell University, 1300 York Ave, New York, New York, 10065, United States of America.|Center of Vascular Biology, Weill Medical College of Cornell University, 1300 York Ave, New York, New York, 10065, United States of America.
authors.forename: Brian D
authors.initials: BD
authors.lastname: Lamon
authors.affiliation: Department of Pathology and Laboratory Medicine, Weill Medical College of Cornell University, 1300 York Ave, New York, New York, 10065, United States of America.|Center of Vascular Biology, Weill Medical College of Cornell University, 1300 York Ave, New York, New York, 10065, United States of America.
authors.forename: George
authors.initials: G
authors.lastname: Moran
authors.affiliation: Department of Cell and Developmental Biology, Weill Medical College of Cornell University, 1300 York Ave, New York, New York, 10065, United States of America.
authors.forename: Tao
authors.initials: T
authors.lastname: Sun
authors.affiliation: Department of Medicine, Weill Medical College of Cornell University, 1300 York Ave, New York, New York, 10065, United States of America.
authors.forename: Antonio M
authors.initials: AM
authors.lastname: Gotto
authors.affiliation: Department of Pathology and Laboratory Medicine, Weill Medical College of Cornell University, 1300 York Ave, New York, New York, 10065, United States of America.|Center of Vascular Biology, Weill Medical College of Cornell University, 1300 York Ave, New York, New York, 10065, United States of America.
authors.forename: David P
authors.initials: DP
authors.lastname: Hajjar
mesh_terms: D064286:ATP Binding Cassette Transporter 1 / Q000235:genetics; D001693:Biological Transport, Active / Q000187:drug effects; D002460:Cell Line; D002784:Cholesterol / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology; D008077:Lipoproteins, LDL / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism*; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism*; D011804:Quinolines / Q000494:pharmacology*; D051782:Sterol Regulatory Element Binding Protein 2 / Q000235:genetics
chemical_list: C577836:ABCA1 protein, human; D064286:ATP Binding Cassette Transporter 1; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008077:Lipoproteins, LDL; C550416:MIRN33a microRNA, human; C569441:MIRN758 microRNA, human; D035683:MicroRNAs; D011804:Quinolines; C497390:SREBF2 protein, human; D051782:Sterol Regulatory Element Binding Protein 2; C099252:oxidized low density lipoprotein; D002784:Cholesterol; C108475:pitavastatin