(Circulation. 2000;102:1296.)
© 2000 American Heart Association, Inc.
Basic Science Reports |
Adiponectin, an Adipocyte-Derived Plasma Protein, Inhibits Endothelial NF-
B Signaling Through a cAMP-Dependent Pathway
From the Department of Internal Medicine and Molecular Science, Graduate School of Medicine, Osaka University, Osaka, and the Cellular Technology Institute, Otsuka Pharmaceutical Co, Ltd, Tokushima (M.M., Y. Ohmoto), Japan. The first 2 authors contributed equally to this work.
Correspondence to Noriyuki Ouchi, MD, Department of Internal Medicine and Molecular Science, Graduate School of Medicine, Osaka University, 2–2, Yamada-oka, Suita, Osaka, 565-0871, Japan. E-mail ouchi{at}imed2.med.osaka-u.ac.jp
Background—Among the many
adipocyte-derived endocrine factors, we found an adipocyte-derived
plasma protein, adiponectin, that was decreased in obesity. We recently
demonstrated that adiponectin inhibited tumor necrosis factor-
(TNF-)–induced expression of endothelial adhesion
molecules and that plasma adiponectin level was reduced in patients
with coronary artery disease (Circulation.
1999;100:2473–2476). However, the intracellular signal by which
adiponectin suppressed adhesion molecule expression was not elucidated.
The present study investigated the mechanism of modulation for
endothelial function by adiponectin.
Methods and Results—The interaction between adiponectin and human
aortic endothelial cells (HAECs) was estimated by cell
ELISA using biotinylated adiponectin. HAECs were preincubated for 18
hours with 50 µg/mL of adiponectin, then exposed to TNF- (10 U/mL)
or vehicle for the times indicated. NF-
B–DNA binding activity was
determined by electrophoretic mobility shift assays. TNF-–inducible
phosphorylation signals were detected by
immunoblotting. Adiponectin specifically bound to HAECs
in a saturable manner and inhibited TNF-–induced mRNA expression of
monocyte adhesion molecules without affecting the interaction between
TNF- and its receptors. Adiponectin suppressed TNF-–induced
IB- phosphorylation and subsequent NF-B
activation without affecting other TNF-–mediated
phosphorylation signals, including Jun N-terminal
kinase, p38 kinase, and Akt kinase. This inhibitory effect
of adiponectin is accompanied by cAMP accumulation and is blocked by
either adenylate cyclase inhibitor or protein
kinase A (PKA) inhibitor.
Conclusions—These observations raise the possibility that
adiponectin, which is naturally present in the blood stream,
modulates the inflammatory response of endothelial
cells through cross talk between cAMP-PKA and NF-B signaling
pathways.
Key Words: endothelium • atherosclerosis • NF-B • adiponectin
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