© 1997 American Heart Association, Inc.
Articles |
Transcriptional Regulation of Inducible Nitric Oxide Synthase in Cultured Neonatal Rat Cardiac Myocytes
From the Second Department of Internal Medicine, Faculty of Medicine, University of Tokyo (Japan).
Correspondence to Koh-ichiro Kinugawa, MD, The Second Department of Internal Medicine, Faculty of Medicine, University of Tokyo, 7 to 3–1 Hongo, Bunkyo-ku, Tokyo, 113, Japan. E-mail kkinugawa{at}medsfgh.ucsf.edu
Abstract Previous work has demonstrated that inducible NO
synthase (iNOS) can be expressed in cardiac myocytes. In this study, we
investigated transcriptional regulation of the iNOS gene in these
cells. Lipopolysaccharide (LPS) induced iNOS mRNA and protein
in cultured neonatal rat cardiac myocytes. H-89,
dexamethasone, herbimycin, genistein,
staurosporine, or pyrrolidine dithiocarbamate (PDTC)
attenuated the iNOS induction by LPS. Forskolin, interleukin (IL)-6,
tumor necrosis factor (TNF)-
, or interferon (IFN)-
enhanced the
LPS-induced iNOS expression. Combined stimulation of IL-6 and TNF-
also induced iNOS. The 5'-upstream sequence of the rat iNOS gene
contains the nuclear factor-
B (NF-B) site, CAAT box, IFN-
activation site (GAS), and IFN regulatory factor (IRF) site. DNase I
footprinting assay revealed that the nuclear factors binding to these
elements were increased by LPS exposure. Transient transfection assay
suggested that these elements were indispensable for transcriptional
regulation of the iNOS induction. Electrophoretic mobility shift assay
revealed that LPS or TNF- increased binding activity for the NF-B
site. A slower-migrating complex binding to the CAAT box gave rise
after exposure to LPS or forskolin. Competition assay suggested that
this slower-migrating complex consisted of a heterodimer between a
member of CAAT box/enhancer binding (C/EBP) protein family and cAMP
responsive element binding protein (CREB). LPS or IL-6 increased
binding complexes for the IRF site, which was compatible with induction
of IRF-1. LPS, IL-6, or IFN- induced a novel binding complex for
GAS, which also existed in the 5'-flanking region of the IRF-1 gene.
These data suggest that (1) iNOS induction simultaneously
requires both NF-B activation and IRF-1 induction, and (2) the
heterodimer between C/EBP and CREB has synergistic effects on the iNOS
induction via the CAAT box.
Key Words: inducible nitric oxide synthase • transcriptional regulation • nuclear factor • cardiac myocyte • neonatal rat
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