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1 Department of Pediatrics, The Evanston Hospital, Northwestern University Medical School, Evanston, Illinois 60201; 2 Department of Pediatrics, University of Minnesota, Minneapolis, Minnesota 55455; 3 Genzyme Corporation, Framingham, Massachusetts 01701-9322; and 4 Department of Anesthesiology and Physiology and Biophysics, University of Alabama at Birmingham, Birmingham, Alabama 35233
Nitric oxide (· NO) has been implicated in a wide range of autocrine and paracrine signaling mechanisms. Herein, we assessed the role of exogenous · NO in the modulation of heterologous gene expression in polarized kidney epithelial cells (LLC-PK1) that were stably transduced with a cDNA encoding human wild-type cystic fibrosis transmembrane conductance regulator (CFTR) under the control of a heavy metal-sensitive metallothionein promoter (LLC-PK1-WTCFTR). Exposure of these cells to 125 µM DETA NONOate at 37°C for 24 h (a chemical · NO donor) diminished Zn2+-induced and uninduced CFTR protein levels by 43.3 ± 5.1 and 34.4 ± 17.1% from their corresponding control values, respectively. These changes did not occur if red blood cells, effective scavengers of · NO, were added to the medium. Exposure to · NO did not alter lactate dehydrogenase release in the medium or the extent of apoptosis. Coculturing LLC-PK1-WTCFTR cells with murine fibroblasts that were stably transduced with the human inducible · NO synthase cDNA gene also inhibited CFTR protein expression in a manner that was antagonized by 1 mM NG-monomethyl-L-arginine in the medium. Pretreatment of LLC-PK1-WTCFTR with ODQ, an inhibitor of guanylyl cyclase, did not affect the ability of · NO to inhibit heterologous CFTR expression; furthermore, 8-bromo-cGMP had no effect on heterologous CFTR expression. These data indicate that · NO impairs the heterologous expression of CFTR in epithelial cells at the protein level via cGMP-independent mechanisms.
peroxynitrite; guanosine 3',5'-cyclic monophosphate; cystic fibrosis; gene transfer; inflammation; nitric oxide synthase; DETA NONOate; cystic fibrosis transmembrane conductance regulator
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