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(Circulation Research. 2006;99:266.)
© 2006 American Heart Association, Inc.

Molecular Medicine

2-Methoxyestradiol, an Estradiol Metabolite, Inhibits Neointima Formation and Smooth Muscle Cell Growth via Double Blockade of the Cell Cycle

Federica Barchiesi, Edwin K. Jackson, Juergen Fingerle, Delbert G. Gillespie, Bernhard Odermatt, Raghvendra K. Dubey

From the Department of Obstetrics and Gynecology (F.B., R.K.D.), Clinic for Endocrinology; Center for Integrative Human Physiology (R.K.D.); and Institute of Clinical Pathology (B.O.), University Hospital Zurich, Switzerland; Center for Clinical Pharmacology (E.K.J., D.G.G., R.K.D.) and Departments of Medicine (E.K.J., D.G.G., R.K.D.) and Pharmacology (E.K.J.), University of Pittsburgh School of Medicine, Pa; and Preclinical Pharma Research 68/209 (J.F.), F. Hoffmann La-Roche, Basel, Switzerland.

Correspondence to Dr Raghvendra K. Dubey, Department of Obstetrics and Gynecology, Clinic for Endocrinology, Frauenklinik, University Hospital Zurich, CH-8091 Zurich, Switzerland. E-mail Raghvendra.Dubey{at}usz.ch

2-Methoxyestradiol (2-ME), an endogenous metabolite of estradiol with no affinity for estrogen receptors, is a potent anticarcinogenic agent (in phase II clinical trials) and mediates the inhibitory effects of estradiol on smooth muscle cell (SMC) growth. Here we studied the intracellular mechanisms by which 2-ME inhibits SMC growth and whether 2-ME prevents injury-induced neointima formation. 2-ME concentrations that inhibit proliferation of cycling human aortic SMCs by 50% blocked cell-cycle progression in G₀/G₁ and in G₂/M phase, as determined by flow cytometry. Consistent with the cell-cycle effects, at a molecular level (Western blots), 2-ME inhibited cyclin D₁ and cyclin B₁ expression; cyclin-dependent kinase (cdk)-1 and cdk-2 activity; and retinoblastoma protein (pRb), extracellular signal-regulated kinase (ERK) 1/2, and Akt phosphorylation. 2-ME also upregulated the Cdk inhibitor p27 and interfered with tubulin polymerization. Moreover, 2-ME augmented COX-2 expression, suggesting that it may also inhibit SMC growth via prostaglandin formation. In rats, treatment with 2-ME abrogated injury-induced neointima formation; decreased proliferating SMCs; downregulated expression of proliferating-cell nuclear antigen (PCNA), c-myc, cyclin D₁, cyclin B₁, phosphorylated Akt, phosphorylated ERK1/2, p21, and pRb; inhibited cdk-1 and cdk-4 activity; and upregulated expression of cyclooxygenase (COX)-2 and p27. Caspase-3 cleavage assay and fluorescence-activated cell-sorting (FACS) analysis showed no evidence of apoptosis in 2-ME-treated SMCs, and TUNEL staining in carotid segments showed no evidence of 2-ME-induced apoptosis in vivo. The antimitotic effects of 2-ME on SMCs are mediated by the inhibition of key cell-cycle regulatory proteins and effects on tubulin polymerization and COX-2 upregulation. These effects of 2-ME most likely contribute to the antivasoocclusive actions of this endogenous compound.

Key Words: restenosis • stents • drugs • remodeling • signal transduction

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Does 2-Methoxyestradiol Represent the New and Improved Hormone Replacement Therapy for Atherosclerosis?

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