ABSTRACT
To investigate the inhibitory specificity of angiotensin converting enzyme (ACE) inhibitors to matrix metalloproteinase (MMP)-9, we predicted molecular interactions between an ACE inhibitor imidapril and MMP-9 active site based on recent X-ray structural analyses. Two binding modes differing in the orientation of imidapril on the active site were identified, and its hydrophobic group appeared to preferentially interact with the S1 site compared with the S1' site. Compared with the lisinopril-MMP-9 model in our previous study, imidapril was stabilized effectively on the active site with less of molecular distortions. We also measured ACE and MMP-9 inhibitory activities of imidapril and lisinopril after myocardial infarction. Imidapril had a stronger inhibitory activity against MMP-9 than lisinopril. These findings show that imidapril inhibits MMP-9 directly like lisinopril and its hydrophobic interactions with the S1 site of MMP-9 would be important for enhancing inhibitory activity.
Subject(s)
Angiotensin-Converting Enzyme Inhibitors/pharmacology , Imidazolidines/pharmacology , Matrix Metalloproteinase Inhibitors , Myocardial Infarction/prevention & control , Angiotensin-Converting Enzyme Inhibitors/metabolism , Animals , Binding Sites , Cricetinae , Heart Ventricles/drug effects , Heart Ventricles/enzymology , Heart Ventricles/pathology , Imidazolidines/metabolism , Lisinopril/pharmacology , Male , Mesocricetus , Models, Molecular , Myocardial Infarction/enzymology , Myocardial Infarction/pathologyABSTRACT
Matrix metalloproteinase-9 activity is dramatically increased during the acute phase after myocardial infarction. However, the relationship between matrix metalloproteinase-9 activity and cardiac dysfunction is unclear. In 1-day post-myocardial infarction hamsters, matrix metalloproteinase-9 activity was significantly increased, while matrix metalloproteinase-2 activity was not increased. A selective matrix metalloproteinase inhibitor, [2S,4S]-N-Hydroxy-5-ethoxymethyloxy-2-methyl-4-[4-phenoxybenzoyl] aminopentanamide (ONO-4817), significantly suppressed matrix metalloproteinase-9 activity 1 day after myocardial infarction. ONO-4817 also significantly prevented the development of cardiac dysfunction and left-ventricular dilatation. Matrix metalloproteinase-9 might play a crucial role in cardiac dysfunction and left-ventricular dilatation during the very acute phase after myocardial infarction.
Subject(s)
Matrix Metalloproteinase Inhibitors , Myocardial Infarction/enzymology , Animals , Cricetinae , Hypertrophy, Left Ventricular/diagnostic imaging , Hypertrophy, Left Ventricular/prevention & control , Male , Matrix Metalloproteinase 2/metabolism , Matrix Metalloproteinase 9/metabolism , Mesocricetus , Myocardial Infarction/diagnostic imaging , Myocardial Infarction/physiopathology , Phenyl Ethers/pharmacology , Time Factors , UltrasonographyABSTRACT
We measured angiotensin-converting enzyme and matrix metalloproteinase-9 activities after myocardial infarction in hamsters and compared the effects of an angiotensin-converting enzyme inhibitor lisinopril with those of an angiotensin receptor blocker candesartan cilexetil after myocardial infarction. Angiotensin-converting enzyme activity was significantly increased 3 and 7 days, but not 1 day after myocardial infarction. Matrix metalloproteinase-9 activity was significantly increased 1 day after myocardial infarction. Lisinopril significantly inhibited both angiotensin-converting enzyme and matrix metalloproteinase-9 activities, but candesartan cilexetil did not. Angiotensin-converting enzyme inhibitors might directly inhibit matrix metalloproteinase-9 activity.
