Imidaprilat inhibits matrix metalloproteinase-2 activity in human cardiac fibroblasts induced by interleukin-1beta via NO-dependent pathway.
BACKGROUND
Angiotensin-converting enzyme (ACE) inhibitors are widely used in treatment of heart failure, but little is known regarding whether ACE inhibitors regulate the activity of matrix metalloproteinases (MMPs) and the tissue inhibitor of MMPs (TIMPs) in cardiac cells. The purpose of this study was to determine the ability and possible signal pathway involved of imidaprilat, an ACE inhibitor, to modulate MMP-2 and TIMP-2 in human cardiac fibroblasts in the presence of interleukin (IL)-1beta.


RESULTS
Using gelatin zymography and RT-PCR and Griess analysis,we found that IL-1beta increased the MMP-2 activity and transcription and nitric oxide(NO) production from supernatant of culture medium. These effects of IL-1beta were inhibited by imidaprilat or the NO synthase inhibitor, L-NMMA. Sodium nitroprusside (SNP), an exogenous NO donor, prevented significantly the effects of imidaprilat on MMP-2 inhibition. Imidaprilat alone didn't affect MMP-2 activity and expression. Neither IL-1beta nor imidaprilat has no effect on TIMP-2 transcription in cardiac fibroblasts.


CONCLUSIONS
The current study demonstrates imidaprilat inhibits MMP-2 activity and expression in human cardiac fibroblasts induced by IL-1beta via NO-dependent pathway. These data suggest that the beneficial effect of ACE inhibitors against left cardiac remodeling and heart failure may be due at least in part to regulating MMPs activity and expression by modulation of NO pathway.
Guo
Xiao-Gang
XG
Department of Cardiovascular Science, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310003 China.
Uzui
Hiroyasu
H
Mizuguchi
Toshihiro
T
Ueda
Takanori
T
Chen
Jun-zhu
JZ
Lee
Jong-Dae
JD
D000704:Analysis of Variance; D002478:Cells, Cultured; D004591:Electrophoresis, Polyacrylamide Gel; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D048289:Imidazolidines / Q000494:pharmacology*; D053583:Interleukin-1beta / Q000378:metabolism* / Q000494:pharmacology; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism*; D061965:Matrix Metalloproteinase Inhibitors; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism*; D009569:Nitric Oxide / Q000378:metabolism*; D011336:Probability; D012313:RNA / Q000032:analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012307:Risk Factors; D012680:Sensitivity and Specificity; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology
D048289:Imidazolidines; D053583:Interleukin-1beta; D061965:Matrix Metalloproteinase Inhibitors; D009569:Nitric Oxide; D012313:RNA; D020778:Matrix Metalloproteinase 2; C078006:imidaprilat