Effects Of Matrix Metalloproteinase On Left Ventricular Remodeling After Myocardial Infarction In Rats

Objective: Characterize the time-course of matrix metalloproteinase (MMP-2, 9) and endogenous tissue inhibitor of MMPs(TIMP-l) up-regulation during left ventricular remodeling following myocardial infarction in rats. We hypothesized that attenuating MMP expression and activity by use of early short-term doxycycline treatment, which is the exogenous inhibitor of MMPs, preserves cardiac structure and function. Methods: The descending left coronary artery of male rats (Sprague-Dawley) was ligated to produce a myocardial infarction model. Nighty rats were randomly divided into the groups of control, myocardial infarction and doxycycline, which were given orally 48 hours before and 48 hours after MI with 30mg/Kg per day. Protein and mRNA extraction was done on left ventricular samples containing scar and myocardium together. Samples were assayed from 1 day to 4 weeks post-Mi. The activity of MMPs was measured by zymography and collagen amount by the method of chloramine T, the ratio of II III collagen was assessed by immunohistochemical stain. Protein and mRNA of MMP-2, 9, TIMP-1 were determined by Western-Blot and RT-PCR. The thickness of left ventricular wall, the diastolic diameter of left ventricular and EF were mensurated by echocardiography (Acuson Sequoia 512). Results: The activities and amount of MMP-2,9 increased significantly after myocardial infarction. Also did the mRNA of MMP-2, 9. The collagen amount increased and the ratio of I/ III decreased. On the contrary, TIMP-1 decreased on the level of protein and mRNA. Doxycycline group versus myocardial infarction group, the activities and amount of MMP-2, 9 decreased significantly; the mRNA of MMP-2, 9 reduced; the collagen amount decreased and the ratio of I/ III increased. The amount of TIMP-1 did not change on the level of protein and mRNA. Conclusions: After myocardial infarction, MMP-2, 9 increased significantly on the level of protein and mRNA; TIMP-1 decreased on the level of protein and mRNA; the collagen amount increased and the ratio of I/ III decreased. These changes may be themajor causes of ventricular remodeling. The effects of doxycycline on the activity of MMP-2, 9, may be one of mechanisms which intervene in the ventricular remodeling following myocardial infarction.