Essential role of the 90-kilodalton heat shock protein in mediating nongenomic estrogen signaling in coronary artery smooth muscle

Guichun Han, Handong Ma, Rajesh Chintala, David J Fulton, Scott A Barman, Richard E. White

Research output: Contribution to journalArticle

23 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)850-855
Number of pages6
JournalJournal of Pharmacology and Experimental Therapeutics
Volume329
Issue number3
DOIs
StatePublished - Jun 1 2009

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HSP90 Heat-Shock Proteins
Smooth Muscle
Coronary Vessels
Estrogens
Nitric Oxide Synthase Type I
Estrogen Receptors
Calcium-Activated Potassium Channels
Vasodilator Agents
Smooth Muscle Myocytes
Endothelium
Estradiol
Swine
Endothelial Cells

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

Cite this

Essential role of the 90-kilodalton heat shock protein in mediating nongenomic estrogen signaling in coronary artery smooth muscle. / Han, Guichun; Ma, Handong; Chintala, Rajesh; Fulton, David J; Barman, Scott A; White, Richard E.

In: Journal of Pharmacology and Experimental Therapeutics, Vol. 329, No. 3, 01.06.2009, p. 850-855.

Research output: Contribution to journalArticle

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