Bradykinin-induced reductions in collagen gene expression involve prostacyclin.
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 PGF1alpha (the stable metabolite of PGI2) release from these cells, in which 1 nmol/L bradykinin produced a 4-fold increase in 6-keto PGF1alpha release. Beraprost (a PGI2 analogue) reduced steady-state proalpha1(I) and proalpha1(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.
Department of Pharmacology, University of California at San Diego, La Jolla 92093-0636, USA.
A M
AM
Gallagher
H
H
Yu
M P
MP
Printz
D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism; D001345:Autoradiography; D015152:Blotting, Northern; D001920:Bradykinin / Q000502:physiology*; D002478:Cells, Cultured; D002851:Chromatography, High Pressure Liquid; D003094:Collagen / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism; D003627:Data Interpretation, Statistical; D003720:Densitometry; D011464:Epoprostenol / Q000032:analysis / Q000378:metabolism*; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D015870:Gene Expression; D007124:Immunoenzyme Techniques; D007213:Indomethacin / Q000494:pharmacology; D009206:Myocardium / Q000378:metabolism*; D011453:Prostaglandins / Q000378:metabolism; D012313:RNA / Q000032:analysis; D012333:RNA, Messenger / Q000032:analysis; D011817:Rabbits
D011453:Prostaglandins; D012333:RNA, Messenger; D016718:Arachidonic Acid; D012313:RNA; D003094:Collagen; D011464:Epoprostenol; D001920:Bradykinin; D007213:Indomethacin