Evolution of matrix metalloprotease and tissue inhibitor expression duringheart failure progression in the infarcted rat

Objective: Characterize the timecourse of matrix metalloproteinase (MMP-1, -2, -3, -7, -9, -11, -12, -13, and -14) and endogenous tissue inhibitors of MMPs (TIMP-1, -2, -3, and -4) upregulation during left Ventricular (LV) re modeling following myocardial infarction (MI) in rats. Methods: The descend ing left coronary artery of male rats (Rattus norvegicus) was ligated to pr oduce a MI. LV function and dilation were assessed from I day to 16 weeks p ost-MI. Protein and mRNA extraction was done on LV samples containing scar and myocardium together. Gelatinase activity was measured by zymography. We sterns were run on the MMPs known to cleave fibrillar collagen in the rat ( MMP-8, -13, and -14) as well as TIMP-1, -2, and -4. Results: Average infarc t size was 38.6+/-1.1%, and produced LV dysfunction and progressive LV dila tion. Thoracic ascites, a marker of congestive heart failure (HF), was not present until 12 weeks post-MI. Upregulation of MMP-2, -8, -9, -13, and -14 and TIMP-1 and TIMP-2 was detected at different timepoints during HF progr ession. Increased MMP protein levels occurred sometimes without a correspon ding elevation in mRNA levels, and increased TIMP mRNA levels without incre ased protein levels. MMP-13 active form was elevated during the first 2 wee ks post-MI while TIMP-1 and TIMP-2, protein levels were not significantly e levated until weeks post-MI. MMP-8 and MMP-14 protein levels increased late r during heart failure progression. Conclusion: MMP/TIMP upregulation evolv es over time following infarction in the rat LV. Some MMPs were significant ly elevated during the first week post-MI (MMP-13, -2, and -9) and another was not until 16 weeks post-MI (MMP-14). The dissociation between LV MMP/TI MP mRNA and protein levels shows that post-translation processing occurs in the rat heart. (C) 2000 Elsevier Science B.V. All rights reserved.