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Article
Essential role of the 90-kilodalton heat shock protein in mediating nongenomic estrogen signaling in coronary artery smooth muscle
Journal of Pharmacology and Experimental Therapeutics
  • Guichun Han
  • Handong Ma
  • Rajesh Chintala
  • David J. R. Fulton
  • Scott A. Barman
  • Richard E. White, Philadelphia College of Osteopathic Medicine
Document Type
Article
Publication Date
1-1-2009
Abstract
Under normal physiological conditions, estrogen is a coronary vasodilator, and this response involves production of NO from endothelial cells. In addition, estrogen also stimulates NO production in coronary artery smooth muscle (CASM); however, the molecular basis for this nongenomic effect of estrogen is unclear. The purpose of this study was to investigate a potential role for the 90-kDa heat shock protein (Hsp90) in estrogen-stimulated neuronal nitric-oxide synthase (nNOS) activity in coronary artery smooth muscle. 17β-Estradiol produced a concentration-dependent relaxation of endothelium-denuded porcine coronary arteries in vitro, and this response was attenuated by inhibiting Hsp90 function with 1 μM geldanamycin (GA) or 100 μg/ml radicicol (RAD). These inhibitors also prevented estrogen-stimulated NO production in human CASM cells and reversed the stimulatory effect of estrogen on calcium-activated potassium (BKCa) channels. These functional studies indicated a role for Hsp90 in coupling estrogen receptor activation to NOS stimulation in CASM. Furthermore, coimmunoprecipitation studies demonstrated that estrogen stimulates bimolecular interaction of immunoprecipitated nNOS with Hsp90 and that either GA or RAD could inhibit this association. Blocking estrogen receptors with ICI182780 (fulvestrant) also prevented this association. These findings indicate an essential role for Hsp90 in nongenomic estrogen signaling in CASM and further suggest that Hsp90 might represent a prospective therapeutic target to enhance estrogen-stimulated cardiovascular protection. Copyright © 2009 by The American Society for Pharmacology and Experimental Therapeutics.
Comments

This article was published in Journal of Pharmacology and Experimental Therapeutics, Volume 329, Issue 3, Pages 850-855.

The published version is available at http://dx.doi.org/10.1124/jpet.108.149112.

Copyright © 2009 JPETS.

Citation Information
Guichun Han, Handong Ma, Rajesh Chintala, David J. R. Fulton, et al.. "Essential role of the 90-kilodalton heat shock protein in mediating nongenomic estrogen signaling in coronary artery smooth muscle" Journal of Pharmacology and Experimental Therapeutics Vol. 329 Iss. 3 (2009) p. 850 - 855
Available at: http://works.bepress.com/richard_white/39/