BRADYKININ-INDUCED REDUCTIONS IN COLLAGEN GENE-EXPRESSION INVOLVE PROSTACYCLIN

Cardiac fibrosis after myocardial infarction and in chronic hypertensi on involves an increase in the synthesis and deposition of collagen wi thin the myocardium. Angiotensin-converting enzyme (ACE) inhibitors li mit hypertrophy and fibrosis; their mechanism of action remains contro versial, although kinins have been implicated to play a role. Because both bradykinin and prostaglandins (PG) have been shown to reduce coll agen gene expression in cardiac fibroblasts, the goal of this study wa s to determine whether the bradykinin effect was mediated through enha nced prostaglandin formation by cardiac fibroblasts. Bradykinin increa sed [H-3]arachidonic acid metabolite release 2.3-fold over control and stimulated a dose-dependent increase in 6-keto PGF(1 alpha) (the stab le metabolite of PGI(2)) release from these cells, in which 1 nmol/L b radykinin produced a 4-fold increase in 6-keto PGF(1 alpha) release. B eraprost (a PGI(2) analogue) reduced steady-state pro alpha 1(I) and p ro alpha 1(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 coll agen biosynthesis via the rabbit cardiac fibroblast involves formation of arachidonic acid metabolites, particularly PGI(2). The results of the present study argue that stabilization of endogenous kinins (as by ACE inhibitors) would enhance prostacyclin production and result in t he attenuation of collagen gene expression, with potential implication s for collagen synthesis and deposition within the myocardium.