Cytokines decrease sGC in pulmonary artery smooth muscle cells via NO-dependent
and NO-independent mechanisms.
Takata, Masao, Galina Filippov, Heling Liu, Fumito Ichinose, Stefan Janssens, Donald B.
Bloch, and Kenneth D. Bloch.
Cardiovascular Research Center and Arthritis Unit, Massachusetts General Hospital,
and Departments of Medicine and Anesthesia, Harvard Medical School, Charlestown,
Massachusetts 02129; and Center for Transgene Technology and Gene Therapy, Flanders
Interuniversity Institute for Biotechnology, and the Cardiac Unit, University Hospital
Gasthuisberg, University of Leuven, Belgium
APStracts 7:0255L, 2000.
Exposure of rat pulmonary artery smooth muscle cells (rPaSMC) to cytokines leads to
nitric oxide (NO) production by NO synthase 2 (NOS2). NO stimulates cGMP synthesis
by soluble guanylate cyclase (sGC), a heterodimer composed of a1- and ß1-subunits.
Prolonged exposure of rPaSMC to NO decreases sGC subunit mRNA and protein levels.
The objective of this study was to determine whether levels of NO produced
endogenously by NOS2 are sufficient to decrease sGC expression in rPaSMC.
Interleukin-1ß (IL-1ß) and tumor necrosis factor-a (TNF-a) increased NOS2 mRNA
levels and decreased sGC subunit mRNA levels. Exposure of rPaSMC to IL-1ß and TNF-
a for 24 h decreased sGC subunit protein levels and NO-stimulated sGC enzyme activity.
l-N6-(1-iminoethyl)lysine (NOS2 inhibitor) or 1H-[1,2,4]oxadiazolo-[4,3-a]quinoxalin-1-
one (sGC inhibitor) partially prevented the cytokine-mediated decrease in sGC subunit
mRNA levels. However, cytokines also decreased sGC subunit mRNA levels in PaSMC
derived from NOS2-deficient mice. These results demonstrate that levels of NO and
cGMP produced in cytokine-exposed PaSMC are sufficient to decrease sGC subunit
mRNA levels. In addition, cytokines can decrease sGC subunit mRNA levels via NO-
independent mechanisms.
Received 30 May 2000; accepted in final form 1 September 2000
APS Manuscript Number L163-0.
Article publication pending Am J Physiol Lung Cell Mol Physiol
ISSN 1080-4757 Copyright 2000 The American Physiological Society.
Published in APStracts on 7 November 2000