© 2000 American Heart Association, Inc.
Molecular Medicine |
Peroxisome Proliferator–Activated Receptor Activators Inhibit Lipopolysaccharide-Induced Tumor Necrosis Factor-
Expression in Neonatal Rat Cardiac Myocytes
From the Third Department of Internal Medicine (H.T., T.N., M.A., T.T., T.S., Y.M.), Chiba University School of Medicine, and Department of Cardiovascular Medicine (T.O., I.K.), University of Tokyo Graduate School of Medicine, Japan.
Correspondence to Hiroyuki Takano, MD, PhD, Third Department of Internal Medicine, Chiba University School of Medicine, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan. E-mail htakano-cib{at}umin.ac.jp
Abstract—Peroxisome
proliferator–activated receptors (PPARs) are transcription
factors belonging to the nuclear receptor superfamily. Recently, PPAR
activators have been shown to inhibit the
production of proinflammatory cytokines in
macrophages or vascular smooth muscle cells. It has been
reported that tumor necrosis factor-
(TNF-) expression is
elevated in the failing heart and that TNF- has a negative inotropic
effect on cardiac myocytes. Therefore, we examined the effects of
PPAR and PPAR
activators on expression of TNF- in
neonatal rat cardiac myocytes. Northern blot analysis revealed
expression of PPAR and PPAR mRNA in cardiac myocytes.
Immunofluorescent staining demonstrated that both PPAR and
PPAR were expressed in the nuclei of cells. When cardiac myocytes
were transfected with PPAR responsive element (PPRE)-luciferase
reporter plasmid, both PPAR and PPAR activators
increased the promoter activity. Cardiomyocytes were stimulated with
lipopolysaccharide (LPS), and the levels of TNF- in the
medium were measured by ELISA. After exposure to LPS, the levels of
TNF- significantly increased. However, pretreatment of myocytes with
PPAR or PPAR activators decreased LPS-induced
expression of TNF- in the medium. Both PPAR and PPAR
activators also inhibited LPS-induced increase in TNF-
mRNA in myocytes. In addition, electrophoretic mobility shift assays
demonstrated that PPAR activators reduced LPS-induced
nuclear factor-
B activation. These results suggest that both PPAR
and PPAR activators inhibit cardiac expression of
TNF- in part by antagonizing nuclear factor-B activity and that
treatment with PPAR activators may lead to improvement in
congestive heart failure.
Key Words: peroxisome proliferator–activated receptor • tumor necrosis factor- • nuclear factor-B • cardiac myocyte
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