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(Circulation Research. 2004;95:228.)
© 2004 American Heart Association, Inc.

Editorials

A New Slice of Pie?

Estrogen Regulation of Plasminogen Activator Inhibitor-1

Nageswara Madamanchi, Xilin Liu, Marschall S. Runge

From the Department of Medicine and Carolina Cardiovascular Biology Center, University of North Carolina, Chapel Hill.

Correspondence to Marschall S. Runge, MD, PhD, Chairman, Department of Medicine, University of North Carolina at Chapel Hill, 3033 OCB, CB 7005, Chapel Hill, NC 27599-7005. E-mail marschall_runge@med.unc.edu

Key Words: plasminogen activator inhibitor-1 • estrogen • estrogen receptor • estrogen response element

An extract of the first 250 words of the full text is provided, because this article has no abstract.

Few clinical studies have impacted clinical care more dramatically than those addressing the role of hormone replacement therapy (HRT) as a strategy to reduce cardiovascular risk. Based on large observational and sound biological studies addressing cardiovascular risk, and on the efficacy of HRT in reducing perimenopausal symptoms, HRT was the standard-of-care for postmenopausal women for many years.¹ Then, as a result of landmark prospectively randomized clinical trials published within the last few years,^2,3 the recommendations changed, such that HRT is no longer routinely prescribed for postmenopausal women.⁴

How could observational studies and biology have been so wrong? The present study by Smith et al⁵ may be a beginning in understanding subtleties implicit in the use of HRT. It is postulated that estrogen has pleiomorphic cardiovascular effects including direct effects on the vessel wall and on extracellular matrix proteins and components,⁶ complex regulation of lipid metabolism⁷ and nitric oxide synthesis, ⁸ and effects on the balance between thrombosis and fibrinolysis⁹—all areas of critical importance in atherogenesis. Many of these effects are mediated via interactions of estrogen with two receptors: ER and ERß.¹⁰ Important downstream events modulated by ER and ERß include regulation of the expression of a number of genes, one of which is plasminogen activator inhibitor-1 (PAI-1), arguably among the most important of the regulators of fibrinolytic balance.

At first glance, one might ask why the present study, which identifies a new estrogen response element (ERE) in the PAI-1 promoter that responds to ER activation, would merit editorial comment. After . . . [Full Text of this Article]