(Hypertension. 1996;27:709-714.)
© 1996 American Heart Association, Inc.
Articles |
Mechanisms of Interleukin-1ß Regulation of Nitric Oxide Synthase in Cardiac Myocytes
From the Hypertension and Vascular Research Division, Henry Ford Hospital, Detroit, Mich.
Correspondence to Dr Margot C. LaPointe, Hypertension and Vascular Research Division, Henry Ford Hospital, 2799 W Grand Blvd, Detroit, MI 48202. E-mail mclapointe@aol.com.
Abstract Cytokines and endotoxin stimulate inducible
NO synthase (iNOS) in different types of cells; however, little is
known about regulatory mechanisms. Using the Griess reagent for nitrite
levels, Western blots for iNOS protein, Northern blots for iNOS mRNA,
and transient transfection studies to monitor transcription, we
determined potential mechanisms involved in interleukin-1ß
stimulation of iNOS in cultured neonatal ventricular
myocytes. When myocytes were treated with interleukin-1ß (5 ng/mL),
nitrite levels increased, and this effect was inhibited 80% by the
specific iNOS inhibitor aminoguanidine. Neither interferon
gamma nor tumor necrosis factor–
alone stimulated nitrite
production. Bacterial endotoxin alone stimulated nitrites and
potentiated the effect of interleukin. To determine whether a tyrosine
kinase–mediated signaling pathway was involved in interleukin
action, we used the inhibitor genistein, which blocked
interleukin-stimulated nitrites, iNOS protein, and iNOS mRNA. To
determine the effect of activation of protein kinase C, we treated
cells with the phorbol ester phorbol 12-myristate 13-acetate
(PMA). PMA decreased both interleukin-stimulated nitrites and iNOS
protein by 40%. To determine the involvement of cyclic
nucleotides, cells were treated with either dibutyryl cAMP
or cGMP. cAMP (1 mmol/L) stimulated iNOS mRNA, protein, and nitrite
production, whereas cGMP had no effect. To test for a direct
effect of interleukin on transcription of the iNOS gene, we transfected
the full-length mouse iNOS 5' regulatory sequences (-1592 to
+160) coupled to a luciferase reporter gene (-1592iNOSLuc).
Interleukin stimulated luciferase activity 1.8±0.2-fold. To determine
whether interleukin also affects iNOS mRNA stability,
interleukin-stimulated iNOS mRNA was allowed to decay in the
presence of the transcription inhibitor actinomycin D. iNOS
mRNA t1/2 (
1 hour) was not affected by interleukin.
Thus, our data suggest that (1) interleukin-1ß is the primary
cytokine in myocyte iNOS regulation and acts predominantly at
the transcriptional level; (2) interleukin stimulation of iNOS mRNA and
protein is coupled to a tyrosine kinase–mediated signaling
pathway; and (3) protein kinase C and cAMP can modify interleukin
signaling by decreasing and increasing iNOS, respectively.
Key Words: cytokines • nitric oxide • ventricular myocytes • tyrosine kinase • cyclic AMP
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