title: Pioglitazone Identifies a New Target for Aneurysm Treatment: Role of Egr1 in an Experimental Murine Model of Aortic Aneurysm.
abstract: Peroxisome proliferator-activated receptor x03B3; agonists have been shown to inhibit angiotensin II (AngII)-induced experimental abdominal aortic aneurysms. Macrophage infiltration to the vascular wall is an early event in this pathology, and therefore we explored the effects of the peroxisome proliferator-activated receptor x03B3; agonist pioglitazone on AngII-treated macrophages. Using microarray-based expression profiling of phorbol ester-stimulated THP-1 cells, we found that a number of aneurysm-related gene changes effected by AngII were modulated following the addition of pioglitazone. Among those genes, polycystic kidney disease 1 (PKD1) was significantly up-regulated (multiple testing corrected p < 0.05). The analysis of the PKD1 proximal promoter revealed a putative early growth response 1 (EGR1) binding site, which was confirmed by chromatin immunoprecipitation (ChIP) and quantitative PCR. Further analysis of publicly available ChIP-sequencing data revealed that this putative binding site overlapped with a conserved EGR1 binding peak present in 5 other cell lines. Quantitative real-time PCR showed that EGR1 suppressed PKD1, while AngII significantly up-regulated PKD1, an effect counteracted by pioglitazone. Conversely, in EGR1 short hairpin RNA lentivirally transduced THP-1 cells, reduced EGR1 led to a significant up-regulation of PKD1, especially after treatment with pioglitazone. In vivo, deficiency of Egr1 in the haematopoietic compartment of mice completely abolished the incidence of CaCl2-induced aneurysm formation.
authors.affiliation: Institute of Cardiovascular and Cell Sciences, St. George's, University of London, London, UK.
authors.forename: Nicoletta
authors.initials: N
authors.lastname: Charolidi
authors.forename: Grisha
authors.initials: G
authors.lastname: Pirianov
authors.forename: Evelyn
authors.initials: E
authors.lastname: Torsney
authors.forename: Stuart
authors.initials: S
authors.lastname: Pearce
authors.forename: Ken
authors.initials: K
authors.lastname: Laing
authors.forename: Axel
authors.initials: A
authors.lastname: Nohturfft
authors.forename: Gillian W
authors.initials: GW
authors.lastname: Cockerill
mesh_terms: D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D017544:Aortic Aneurysm, Abdominal / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control*; D001483:Base Sequence; D001665:Binding Sites; D002122:Calcium Chloride; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D051766:Early Growth Response Protein 1 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods; D005786:Gene Expression Regulation; D006801:Humans; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D047495:PPAR gamma / Q000819:agonists / Q000378:metabolism; D000077205:Pioglitazone; D011401:Promoter Regions, Genetic; D034622:RNA Interference; D015398:Signal Transduction / Q000187:drug effects; D050396:TRPP Cation Channels / Q000235:genetics / Q000378:metabolism; D045162:Thiazolidinediones / Q000494:pharmacology*; D013997:Time Factors; D014162:Transfection
chemical_list: D000804:Angiotensin II; D002122:Calcium Chloride; D051766:Early Growth Response Protein 1; D047495:PPAR gamma; D000077205:Pioglitazone; D050396:TRPP Cation Channels; D045162:Thiazolidinediones; C497325:EGR1 protein, human; C486109:Egr1 protein, mouse