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Permanent URL to this publication: http://dx.doi.org/10.5167/uzh-38600

Barchiesi, F; Lucchinetti, E; Zaugg, M; Ogunshola, O O; Wright, M; Meyer, M; Rosselli, M; Schaufelberger, S; Gillespie, D G; Jackson, E K; Dubey, R K (2010). Candidate genes and mechanisms for 2-methoxyestradiol-mediated vasoprotection. Hypertension, 56(5):964-972.

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Abstract

2-Methoxyestradiol (2-ME; estradiol metabolite) inhibits vascular smooth muscle cell (VSMC) growth and protects against atherosclerosis and vascular injury; however, the mechanisms by which 2-ME induces these actions remain obscure. To assess the impact of 2-ME on biochemical pathways regulating VSMC biology, we used high-density oligonucleotide microarrays to identify differentially expressed genes in cultured human female aortic VSMCs treated with 2-ME acutely (4 hours) or long term (30 hours). Both single gene analysis and Gene Set Enrichment Analysis revealed 2-ME-induced downregulation of genes involved in mitotic spindle assembly and function in VSMCs. Also, Gene Set Enrichment Analysis identified effects of 2-ME on genes regulating cell-cycle progression, cell migration/adhesion, vasorelaxation, inflammation, and cholesterol metabolism. Transcriptional changes were associated with changes in protein expression, including inhibition of cyclin D1, cyclin B1, cyclin-dependent kinase 6, cyclin-dependent kinase 4, tubulin polymerization, cholesterol and steroid synthesis, and upregulation of cyclooxygenase 2 and matrix metalloproteinase 1. Microarray data suggested that 2-ME may activate peroxisome proliferator-activated receptors (PPARs) in VSMCs, and 2-ME has structural similarities with rosiglitazone (PPARγ agonist). However, our finding of weak activation and lack of binding of 2-ME to PPARs suggests that 2-ME may modulate PPAR-associated genes via indirect mechanisms, potentially involving cyclooxygenase 2. Indeed, the antimitogenic effects of 2-ME at concentrations that do not inhibit tubulin polymerization were blocked by the PPAR antagonist GW9662 and the cyclooxygenase 2 inhibitor NS398. Finally, we demonstrated that 2-ME inhibited hypoxia-inducible factor 1α. Identification of candidate genes that are positively or negatively regulated by 2-ME provides important leads to investigate and better understand the mechanisms by which 2-ME induces its vasoprotective actions.

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > University Hospital Zurich > Clinic for Gynecology
04 Faculty of Medicine > University Hospital Zurich > Clinic for Reproductive Endocrinology
05 Vetsuisse Faculty > Institute of Veterinary Physiology
04 Faculty of Medicine > Center for Integrative Human Physiology
DDC:570 Life sciences; biology
610 Medicine & health
Language:English
Date:November 2010
Deposited On:23 Nov 2010 15:20
Last Modified:27 Nov 2013 22:30
Publisher:American Heart Association
ISSN:0194-911X
Free access at:Publisher DOI. An embargo period may apply.
Publisher DOI:10.1161/HYPERTENSIONAHA.110.152298
PubMed ID:20921434
Citations:Web of Science®. Times Cited: 8
Google Scholar™
Scopus®. Citation Count: 10

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