© 1999 American Heart Association, Inc.
Original Contribution |
Tumor Necrosis Factor-
Upregulates Angiotensin II Type 1 Receptors on Cardiac Fibroblasts
From the Department of Medicine, Division of Cardiology, University of California, San Diego Medical Center, San Diego, Calif.
Correspondence to Barry Greenberg, MD, Department of Medicine/Cardiology, UCSD Medical Center, 200 W Arbor Dr, San Diego, CA 92103-8411. E-mail bgreenberg{at}ucsd.edu
Abstract—Angiotensin
II (Ang II) plays an important role in post–myocardial infarction (MI)
remodeling. Most Ang II effects related to remodeling involve
activation of the type 1 receptor (AT1). Although
the AT1 receptor is upregulated on cardiac fibroblasts
post-MI, little is known about the mechanisms involved in the process.
Consequently, we tested whether growth factors known to be present
in the remodeling heart increased AT1 mRNA levels. Using
quantitative competitive reverse transcription–polymerase chain
reaction, we found that norepinephrine, endothelin, atrial
natriuretic peptide, and bradykinin had no significant
effect on AT1 mRNA levels. Ang II, transforming growth
factor-ß1, and basic fibroblast growth factor reduced
AT1 mRNA levels (P<0.02). Tumor necrosis
factor-
(TNF-), however, produced a marked increase in
AT1 mRNA. After 24 hours of TNF- incubation,
AT1 mRNA increased by 5-fold above control levels
(P<0.01). The EC50 for the TNF- effect
was 4.6 ng/mL (0.2 nmol/L). Interleukin (IL)-1ß caused a 2.4-fold
increase, whereas IL-2 and IL-6 had no significant effect. Studies of
TNF- enhancement of AT1 mRNA levels demonstrate that the
increase was not due to a change in transcript stability. TNF-
treatment for 48 hours also resulted in a 3-fold increase in
AT1 surface receptor and a 2-fold increase in Ang
II–induced production of inositol phosphates. The present
findings provide evidence for TNF- regulation of AT1
receptor density on cardiac fibroblasts. Because TNF- concentration
and AT1 receptor density increase in the
myocardium after MI, these results raise the possibility
that TNF- modulates post-MI remodeling by enhancing Ang II effects
on cardiac fibroblasts.
Key Words: AT1 • cardiac fibroblast • tumor necrosis factor- • post–myocardial infarction remodeling
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