Experimental Research About The Correlation Of MMPs/TIMPs With Myocardial Ischemia-reperfusion Injury

Objective To investigate the changes and significance of MMP-1,-2,-9 and TIMP-1 in myocardium of rats during myocardial ischemia-reperfusion(I/R). Simultaneously, to study the effects of pretreated with doxycycline and fluvastatin on ischemia-reperfused myocardium in rats.Methods The models of I/R were successfully established in anaesthetized rats, and the rats sham-operated were used as control. Immunohistochemical SABC method and computerized image analysis were used to observe alterations of MMP-1, -2, -9 and TIMP-1 protein in myocardium of rats. The function of left ventricle were measured by instrument of collecting physiological signals. The activities of CK, LDH ,MPO and the size of myocardial infarction were respectively assayed by colorimetry and weighting method; ultrastructures of myocardium were observed by electron microscope.Results The data have showed that there were obviously deterioration in the function of left ventricle and marked increase in the activities of CK, LDH, MPO after ischemia-reperfusion, and changes of time-dependent were observed during ischemia-reperfusion. On the other hand, all of them reached peak at the second hour of reperfusion.The expression of MMP-1,-9 in myocardium of rats were significantly enhanced after ischemia-reperfusion and reached peak respectively at the first or second hour of reperfusion. In addition, the expression of MMP-1,-9 were correlated negatively with the changes of mechanical function during myocardial ischemia-reperfusion. The expression of TIMP-1 was notably decreased after ischemia , and decreased much more at half hour of reperfusion than after ischemia but non-reperfusion. Moreover, there were no differences in posterior-time of reperfusion compared with at half hour of reperfusion. Otherwise,the MMP-2 could not be detected by immunohistochemistry with the anti-MMP-2 antibody applied. Furthermore, we found that the function of left ventricle and ultrastructure of myocardium were improved, and the activities of CK, LDH, MPO and the size of myocardial infarction were decreased after 60 minutes of ischemia and two hours of reperfusion, and the expression of MMP-1, -9 were obviously decreased in group pretreated-doxycycline and pretreated-fluvastatin. Moreover, the expression of TIMP-1 was upregulated after the rats were pretreated with fluvastatin.Conclusions MMPs and the disorder of MMPs/TIMPs could play a key roles in myocardial ischemia-reperfusion injury. Doxycycline and Fluvastatin could protect the myocardium after ischemia-reperfusion, and the cholesterol-independent protective effects of statins could include inhibit MMPs and upregulate TIMPs. The control of MMPs/TIMPs as a potential target for myocardial ischemia-reperfusion injury are speculated.