From the Department of Pharmacology, University of California at San
Diego, La Jolla, Calif.
Abstract—Cardiac fibrosis after
myocardial infarction and in chronic hypertension involves an increase
in the synthesis and deposition of collagen within the
myocardium. Angiotensin-converting enzyme (ACE)
inhibitors limit hypertrophy and fibrosis;
their mechanism of action remains controversial, although kinins have
been implicated to play a role. Because both bradykinin and
prostaglandins (PG) have been shown to reduce collagen gene
expression in cardiac fibroblasts, the goal of this study was to
determine whether the bradykinin effect was mediated through enhanced
prostaglandin formation by cardiac fibroblasts. Bradykinin
increased [3H]arachidonic acid metabolite
release 2.3-fold over control and stimulated a dose-dependent increase
in 6-keto PGF1
© 1998 American Heart Association, Inc.
Scientific Contributions
Bradykinin-Induced Reductions in Collagen Gene Expression Involve Prostacyclin
(the stable metabolite of
PGI2) release from these cells, in which 1 nmol/L
bradykinin produced a 4-fold increase in 6-keto PGF1
release. Beraprost (a PGI2 analogue) reduced steady-state
pro1(I) and pro1(III) collagen mRNA levels by 35.6±6.6% and
34.2±10.0%, respectively. Bradykinin-induced reductions in collagen
type I and III gene expression were reversed by pretreatment with
indomethacin. Our results indicate that one mechanism
by which bradykinin modulates collagen biosynthesis via the rabbit
cardiac fibroblast involves formation of arachidonic
acid metabolites, particularly PGI2. The results of the
present study argue that stabilization of endogenous
kinins (as by ACE inhibitors) would enhance prostacyclin
production and result in the attenuation of collagen gene
expression, with potential implications for collagen synthesis and
deposition within the myocardium.
Key Words: bradykinin • collagen • prostaglandins • fibroblasts • rabbits
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