Candidate Genes and Mechanisms for 2-Methoxyestradiol-Mediated Vasoprotection

被引:25
作者
Barchiesi, Federica [1 ]
Lucchinetti, Eliana [7 ,8 ]
Zaugg, Michael [7 ,8 ]
Ogunshola, Omolara O. [2 ,3 ]
Wright, Matthew [4 ]
Meyer, Markus [4 ]
Rosselli, Marinella [1 ]
Schaufelberger, Sara [1 ]
Gillespie, Delbert G. [5 ]
Jackson, Edwin K. [5 ,6 ]
Dubey, Raghvendra K. [3 ,5 ,6 ]
机构
[1] Univ Zurich Hosp, Dept Obstet & Gynecol, Clin Reprod Endocrinol, CH-8091 Zurich, Switzerland
[2] Univ Zurich, Inst Vet Physiol, Vetsuisse Fac, Zurich, Switzerland
[3] Univ Zurich, Zurich Ctr Integrat Human Physiol, Zurich, Switzerland
[4] Hoffmann La Roche AG, Metab & Vasc Dis, Basel, Switzerland
[5] Univ Pittsburgh, Sch Med, Dept Med, Ctr Clin Pharmacol, Pittsburgh, PA USA
[6] Univ Pittsburgh, Sch Med, Dept Pharmacol & Chem Biol, Pittsburgh, PA USA
[7] Univ Alberta, Dept Anesthesiol & Pain Med, Edmonton, AB, Canada
[8] Univ Alberta, Cardiovasc Res Ctr, Edmonton, AB, Canada
基金
美国国家卫生研究院; 瑞士国家科学基金会;
关键词
2-methoxyestradiol; PPAR; vascular smooth muscle cells; microarray analysis; SMOOTH-MUSCLE-CELLS; HYPOXIA-INDUCIBLE FACTOR-1-ALPHA; CORONARY-ARTERY-DISEASE; METHOXYESTRADIOLS MEDIATE; ESTRADIOL METABOLITE; GROWTH; EXPRESSION; ATHEROSCLEROSIS; IDENTIFICATION; PROLIFERATION;
D O I
10.1161/HYPERTENSIONAHA.110.152298
中图分类号
R6 [外科学];
学科分类号
1002 ; 100210 ;
摘要
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 (PPAR gamma 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 1 alpha. 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. (Hypertension. 2010;56:964-972.)
引用
收藏
页码:964 / U489
页数:31
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