© 1997 American Heart Association, Inc.
Articles |
Interleukin-1ß Inhibits Phospholamban Gene Expression in Cultured Cardiomyocytes
From the Division of Cardiology, University of Pittsburgh (Pa) Medical Center.
Correspondence to Charles F. McTiernan, PhD, Division of Cardiology, University of Pittsburgh, Biomedical Science Tower 1744.1, 200 Lothrop St, Pittsburgh, PA 15213. E-mail mctier{at}card2.cath.upmc.edu
Abstract Phospholamban is a key regulatory protein that
defines diastolic function. Proinflammatory
cytokines interleukin-1ß (IL-1ß) and tumor necrosis
factor-
(TNF-) can depress contractility and
intracellular Ca2+ currents and transients. An alteration
in phospholamban expression is a possible pathway by which these
cytokines modulate cardiac function. To test this hypothesis,
primary cultures of neonatal rat cardiomyocytes were
incubated with IL-1ß, TNF-, or both, and the level of
phospholamban transcripts was examined by Northern blot
analyses. Phospholamban transcript levels were decreased
50% (P<.0001) in cells exposed to 2 ng/mL IL-1ß (20
hours), whereas TNF- had no effect. Western blot analyses
showed that IL-1ß also reduced phospholamban protein levels (60% of
control, P<.0001). The effects on transcript levels were
gene specific; IL-1ß induced transcripts for inducible NO synthase
(iNOS), did not alter GAPDH transcripts, and reduced sarcoplasmic
reticulum Ca2+-ATPase (65% of control,
P<.001) transcripts. Cardiomyocytes treated with
IL-1ß showed no alterations in basal contractile
parameters (maximum velocity of contraction and relaxation
and maximal amplitude of contraction) but were unresponsive to
ß-adrenergic stimulation. Studies performed in the presence of
second-messenger inhibitors showed that the effect of
IL-1ß on phospholamban transcript levels was blocked by
dexamethasone, was insensitive to inhibitors of
iNOS, cyclooxygenase, or tyrosine kinases, but was
enhanced by the addition of the protein kinase inhibitor
staurosporine. These data demonstrate that IL-1ß alters
the expression of phospholamban, a key regulator of cardiac
contractility, at both the transcript and protein
levels. The results suggest novel mechanisms by which IL-1ß may
modify cardiac function.
Key Words: molecular biology • cardiomyocyte • proinflammatory cytokine • RNA • phospholamban
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