Estrogen stimulates heat shock protein 90 binding to endothelial nitric oxide synthase in human vascular endothelial cells. Effects on calcium sensitivity and NO release.
Estradiol (E(2)) causes endothelium-dependent vasodilation, mediated, in part, by enhanced nitric oxide (NO) release. We have previously shown that E(2)-induced activation of endothelial nitric oxide synthase (eNOS) reduces its calcium dependence. This pathway of eNOS activation is unique to a limited number of stimuli, including shear stress, the response to which is herbimycin-inhibitable. Consistent with this, herbimycin and geldanamycin pretreatment of human umbilical vein endothelial cells (HUVEC) abrogated E(2)-stimulated NO release and cGMP production, respectively. These benzoquinone ansamycins are potent inhibitors of Hsp90 function, which has recently been shown to play a role in stimulus-dependent eNOS activation. As in response to shear, E(2) induced an Hsp90-eNOS association, peaking at 30 min and completely inhibited by the conventional estrogen receptor antagonist ICI 182,780. These findings suggest that Hsp90 plays an important role in the rapid, estrogen receptor-mediated modulation of eNOS activation by estrogen.
Russell
K S
KS
Division of Cardiovascular Medicine and Molecular Cardiobiology, Boyer Center for Molecular Medicine, New Haven, Connecticut 06536-0812, USA.
Haynes
M P
MP
Caulin-Glaser
T
T
Rosneck
J
J
Sessa
W C
WC
Bender
J R
JR
D016227:Benzoquinones; D002118:Calcium / Q000378:metabolism*; D002478:Cells, Cultured; D006152:Cyclic GMP / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004958:Estradiol / Q000494:pharmacology*; D005260:Female; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism*; D006801:Humans; D047029:Lactams, Macrocyclic; D009569:Nitric Oxide / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D052250:Nitric Oxide Synthase Type III; D011485:Protein Binding; D011809:Quinones / Q000494:pharmacology; D017828:Rifabutin / Q000031:analogs & derivatives
D016227:Benzoquinones; D004791:Enzyme Inhibitors; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; D011809:Quinones; D017828:Rifabutin; D009569:Nitric Oxide; D004958:Estradiol; C020754:herbimycin; C496314:NOS3 protein, human; D019001:Nitric Oxide Synthase; D052250:Nitric Oxide Synthase Type III; D006152:Cyclic GMP; D002118:Calcium