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ToxSci Advance Access published online on March 25, 2003
Toxicological Sciences, doi:10.1093/toxsci/kfg062
Toxicological Sciences © Society of Toxicology 2003; all rights reserved
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Received November 18, 2002; accepted February 8, 2003
© 2003 Society of Toxicology

In Vitro Toxicology and Alternative Testing

Trichloroethylene Decreases Heat Shock Protein 90 Interactions with Endothelial Nitric Oxide Synthase: Implications for Endothelial Cell Proliferation

Jingsong Ou 1*, Zhijun Ou 1, D. Gail McCarver 2, Ronald N. Hines 2, Keith T. Oldham 3, Allan W. Ackerman 4, Kirkwood A. Pritchard Jr5

1 Department of Surgery, Division of Pediatric Surgery, Medical College of Wisconsin, Milwaukee, Wisconsin 53226; Cardiovascular Center, Medical College of Wisconsin, Milwaukee, Wisconsin 53226
2 Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, Wisconsin 53226; Department of Pediatrics, Medical College of Wisconsin, Milwaukee, Wisconsin 53226
3 Department of Surgery, Division of Pediatric Surgery, Medical College of Wisconsin, Milwaukee, Wisconsin 53226; Cardiovascular Center, Medical College of Wisconsin, Milwaukee, Wisconsin 53226; Free Radical Research Center, Medical College of Wisconsin, Milwaukee, Wisconsin 53226
4 Department of Surgery, Division of Pediatric Surgery, Medical College of Wisconsin, Milwaukee, Wisconsin 53226
5 Department of Surgery, Division of Pediatric Surgery, Medical College of Wisconsin, Milwaukee, Wisconsin 53226; Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, Wisconsin 53226; Cardiovascular Center, Medical College of Wisconsin, Milwaukee, Wisconsin 53226; Free Radical Research Center, Medical College of Wisconsin, Milwaukee, Wisconsin 53226

* To whom correspondence should be addressed. E-mail: JOU{at}mcw.edu.


  Abstract

Trichloroetheylene (TRI) is an environmental pollutant that has been linked to congenital heart defects (CHD). Endothelial nitric oxide synthase (eNOS) generation of nitric oxide (•NO) plays an important role in endothelial cell proliferation, which is considered essential for normal blood vessel growth and development. We hypothesized that TRI alters the balance of •NO and superoxide anion (O2•-) to impair endothelial cell proliferation. Proliferating endothelial cells were pretreated with TRI (5 µM) and then stimulated with the calcium ionophore, A23187 (5 µM), to determine changes in endothelial cell and eNOS function with respect to •NO and O2•- generation. Immunoblots of eNOS, phospho-eNOS at serine 1179 (S1179) and the levels of associated heat shock protein 90 (hsp90) were used to define the activation state of eNOS. The effects of TRI (0.05-100 µM) on vascular endothelial growth factor (VEGF, 0.58 nM) induced endothelial cell proliferation were determined from cell counts. TRI decreased A23187-stimulated nitrite + nitrate production from 1.99±0.90 to 0.89±0.51 pmol/mg protein (p<0.05; n=6). In controls, L-NAME increased A23187-stimulated O2•- production from 0.130±0.089 to 0.214±0.071 nmol/min/mg protein (p<0.05; n=5). In TRI-treated cultures, however, L-NAME decreased A23187-stimulated O2•- production from 0.399±0.121 to 0.199±0.055 nmol/min/mg protein (p<0.05; n=5). TRI decreased hsp90 associated with eNOS by 46.7% and inhibited VEGF-stimulated endothelial cell proliferation by 12 to 35%. These data show that TRI alters hsp90 interactions with eNOS and induces eNOS to shift from •NO to O2•- generation. Our findings provide new insight into how TRI alters endothelial and eNOS function to impair VEGF-stimulated endothelial proliferation. Such changes in endothelial function may play an important role in the development of congenital heart defects.


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