Protective Effects Of Metoprolol In Different Dose On Matrix Metalloproteinase-2 And Its Tissue Inhibitor-mediated Ventricular Remodeling After MI

OBJECTIVE: To investigate the role of metalloproteinase (MMP-2), tissue inhibitor of metalloproteinase(TIMP-2) and transforming growth factorβ1 (TGF-β1 ) in acute myocardial infarction and extracellular matrix remodeling and comparative effects of Metoprolol in large and middle dose in preventing ventricular remodeling in rats model.METHODS: Rats surviving 24h after AMI induced by left anterior descending branch ligation were randomized to large dose metoprolol group(MI-ML), middle dose metoprolol group(MI-MM) and control group compared(MI) with sham-operated group(SH). Large dose metoprolol group were given metoprolol 30mg.(kg.d)-1 . Middle dose metoprolol group were given metoprolol 5mg.(kg.d)-1. Control and sham-operated group were given saline 15ml.(kg.d)-1. Observe the ventricular remodeling index, the expression of myocardium MMP-2, TIMP-2和TGF-β1 protein examined by immunohistochemical analysis at the end of the forth week.RESULTS: Compared with sham-operated rats, the protein expression of MMP-2, TIMP-2 and TGF-β1 and MMP-2/TIMP-2 ratio were significantly increased (P<0.01), while left ventricular(LV) end diastolic pressure(LVEDP), LV relative weight(LVRW), right ventricular relative weight(RVRW) and collagen volume fraction(CVF) were significantly increased(all P<0.01); whereas - d p / d t ,+ d p / d t were significantly reduced(all P<0.01) at 4 weeks after AMI, indicating that LV remodeling and LV function decreased. After four-week metoprolol treatment in no matter what dose , the protein expression of MMP-2, and TGF-β1 and MMP-2/TIMP-2 ratio were significantly reduced(all P<0.01).The protein expression of TIMP-2 were higher in large dose metoprolol group than in MI control group,but the increasing extent of TIMP-2 is less than that of MMP-2 while there were no significantly changes in the expression of TIMP-2 in middle dose metoprolol group. Metoprolol in no matter what dose effectively and dose-dependently revert to balance of MMP-2/TIMP-2, while left ventricular (LV) end diastolic pressure(LVEDP), LV relative weight(LVRW), right ventricular relative weight(RVRW) and collagen volume fraction (CVF) were significantly ruduced(all P<0.01) ; whereas -dp/dt,+dp/dtwere significantly increased (all P<0.01) at 4 weeks after AMI..CONCLUSION: Metoprolol in no matter what dose effectively and dose-dependently can prevent left ventricular extracellular matrix remodeling, which is associated with the attenuation of myocardial MMP-2 and TGF-β1 and the revertion of balance of MMP-2/TIMP-2.