© 1996 American Heart Association, Inc.
Articles |
Salicylate or Aspirin Inhibits the Induction of the Inducible Nitric Oxide Synthase in Rat Cardiac Fibroblasts
From the Department of Biochemistry and Pathology, Boston (Mass) University School of Medicine.
Correspondence to Peter Brecher, PhD, Department of Biochemistry and Pathology, Boston University School of Medicine, Whitaker Cardiovascular Institute, 80 East Concord St, Boston, MA 02118. E-mail pbrecher@acs.bu.edu.
Abstract To determine if fibroblasts are a source of NO
in inflammatory myocardial diseases, we have studied the effect of
cytokines on the inducible NO synthase (iNOS) in neonatal
cardiac fibroblasts and tested whether nonsteroidal
anti-inflammatory drugs can diminish the induction of iNOS. In
primary cultures, interferon gamma (IFN), interleukin-1ß (IL-1), or
tumor necrosis factor-
(TNF) separately did not stimulate nitrite
production, whereas IFN combined with IL-1 or TNF
synergistically induced iNOS, both at the level of steady state mRNA
and nitrite accumulation. Steady state mRNA levels for iNOS were
obvious as early as 3 hours after the addition of IFN+TNF and remained
elevated for at least 72 hours. Sodium salicylate inhibited
cytokine-induced nitrite accumulation in a time- and
dose-dependent manner (IC50, 750 µmol/L). The
inhibition was reversible and occurred when salicylate was added either
before or after cytokine induction. Aspirin (1 mmol/L) also
inhibited nitrite production, whereas
indomethacin (25 µmol/L) or acetaminophen
(100 µmol/L) did not. TNF, either alone or combined with IFN,
significantly stimulated prostaglandin
E2, which was inhibited by either salicylate (4
mmol/L) or indomethacin (25 µmol/L). Salicylate, when
given either before or after IFN+TNF, reduced mRNA levels of iNOS
induced by cytokines. Salicylate did not affect iNOS enzymatic
activity when added to the cytosolic lysate, although it was able to
reduce enzymatic activity to 32% of induced levels when given to
intact cells. These studies implicate cardiac fibroblasts as a source
of NO in inflammatory cardiac diseases and suggest a possible
therapeutic role for salicylate and aspirin in diminishing the steady
state levels of iNOS mRNA.
Key Words: nitric oxide • fibrosis • prostaglandins • cell culture
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